Near Infrared Fluorescent Technique for Sentinel Lymph Node Mapping in Endometrial Cancer
Phase: NA
Conditions: Endometrial Neoplasms
Sponsor: Region Skane

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Title page 
 
 
Near Infrared Fluorescent Technique for Sentinel Lymph Node Mapping in 
Endometrial Cancer  
 
 
Version 1.3                                                                                           170215 
 
The study consist of two subsets of patients  
 
-High risk endometrial cancer ( HREC) in whom a full pelvic lymphadenectomy is 
performed after removal of sentinel lymph nodes 
 
-Low risk endometrial (LREC) cancer or comorbid HREC in whom no further 
lymphadenectomy is performed after removal of sentinel lymph nodes 
  
Hence two study protocol with different sample size analyses 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 

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Sentinel lymph node detection in high risk endometrial cancer. 
A prospective non-randomized trial using an anatomically based 
surgical algorithm. 
 
 
Protocol identification number: SLN-HREC Version 1.3 
 
 
 
 
 
 
Principal Investigator 
Jan Persson MD PhD Associate Professor 
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology 
Skåne University Hospital Lund 
Lund University Faculty of Medicine, Department of Clinical Sciences, 
Obstetrics and Gynecology, Lund Sweden 
 
SE-22185 Lund, Sweden 
(ph) +46733522080 
(fax) +4646156868 
Email: jan.persson@med.lu.se 
 
 
 
 
 
 
 
 
 
Confidentiality: This document contains confidential information that must not be disclosed 
to anyone other than Sponsor, Investigator Team and members of the Ethics Committees, 
unless authorized to do so.  
 
 

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Contact information 
 
Principal investigator: Jan Persson MD PhD Associate Professor  
Department of obstetrics and Gynecology, Division of Gynecologic Oncology 
Skåne University Hospital Lund 
SE-22185 Lund, Sweden 
(ph) +46733522080 
(fax) +4646156868 
Email: jan.persson@med.lu.se  
 
Site Principal Investigator, Karolinska University Hospital: Henrik Falconer MD PhD 
Associate Professor 
Department of Obstetrics and Gynecology Karolinska University Hospital 
Division of Gynecologic Oncology 
Karolinska University Hospital 
171 76 Stockholm, Sweden 
(ph) +468-517 700 00 
Email: henrik.falconer@sll.se 
 
Study Coordinator: Michele Bollino MD 
Department of obstetrics and Gynecology, Division of Gynecologic Oncology 
Skåne University Hospital Lund 
SE-22185 Lund, Sweden 
(ph)+4646172093 
(fax) +4646156868 
Email: Michele.bollino@med.lu.se 
 
Study Statistician: Filip Mörk. Faculty of Engineering, Lund University. 
 
 
 
 
 
 
 
 
Table of Contents 
 

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1. List of abbreviations 
2. Synopsis 
3. Background 
   3.1 Surgical staging of endometrial cancer 
   3.2 The sentinel lymph node biopsy concept in endometrial cancer 
4. Rationale for study 
5. Objective 
   5.1 Primary objective 
   5.2 Secondary objective 
6. Study plan and design 
7. Study treatment 
   7.1 Overview of treatment 
   7.2 Standard treatment 
      7.2.1 Surgical procedures 
      7.2.2 Definition of anatomical boundaries for lymphadenectomy 
   7.3 Intervention 
      7.3.1 Indocyanine green 
         7.3.1.1 Drug information 
         7.3.1.2 Injection of indocyanine green 
      7.3.2 Sentinel node identification 
         7.3.2.1 Identification and definition of potential paraaortic sentinel nodes 
      7.3.3 Anatomic description of lymphatic pathways draining the uterus 
   7.4 Treatment modifications 
   7.5 Participating surgeons 
8. Evaluation of histopathology 
   8. 1 Histopathologic evaluation of the sentinel nodes  
      8.1.2 Classification of tumor size in sentinel nodes 
   8.2   Histopathologic evaluation of non-sentinel lymph nodes 
9. Outcomes 
   9.1 Primary outcome 
   9.2 Secondary outcomes 
10. Patient enrollment 
   10.1 Inclusion criteria 
   10.2 Exclusion criteria 
11. Evaluation criteria 
12. Adverse events 
   12.1 Definition 
13. Study monitoring/study accrual oversight 
   13.1 Duration of study 
14. Data management 
   14.1 Early study closure 

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   14.2 Protocol deviations 
15. Statistical considerations 
16. Ethical considerations 
   16.1 Informed consent 
   16.2 Patient protection and Good clinical practice 
   16.3 Subject identification 
17. Trial Sponsor and financing 
18. Publications 
19. Approvals 
20. References/Bibliography 
21. Appendices 
    
    
 
       
 
    
 
        
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. List of Abbreviations 
 

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AJCC 
American joint committee on cancer 
CT 
Computerized tomography 
FIGO 
Int. federation of Obstetrics& gynecology 
ICG 
Indocyanine Green 
IPP 
Infundibulopelvic pathway 
ITC  
Isolated tumor cells 
LPP 
Lower paracervical pathway 
SAE 
Serious adverse event 
SLN 
Sentinel lymph node 
UPP 
Upper paracervical pathway 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2. Synopsis 
 
Protocol Title 
Sentinel lymph node detection in high risk endometrial 
cancer. A prospective non-randomized trial using an 
anatomically based surgical algorithm. 
 
Indication 
Endometrial cancer presumed stage I-II with high risk features defined 
as: Endometrioid grade 3,Endometrioid grade 1 or 2 with >50% 
myometrial invasion or cervical stroma invasion, Non-endometrioid 
histology, Non-diploid cytometry (until February 14, 2017). 
Primary objective 
This study aims to evaluate sensitivity and false negative rates for a 
pelvic sentinel node concept based on a defined surgical algorithm and 
with a clear definition of SLN based on uterine lymphatic anatomy.  
Secondary objectives 
To evaluate technical success rated including reinjection of tracer in case 
of non-display of a pathway. To evaluate perioperative outcomes, 
adverse events, postoperative complications and proportion isolated 
paraaortic lymph node metastases when pelvic sentinel lymph node 
mapping is performed 
Study Design 
Non-randomized controlled trial 
Planned sample size 
250-550 women 
Inclusion criteria 
( all fulfilled) 
-Women of age 18 years and older at the time of informed consent. 
-Women with a pathologically proven endometrial carcinoma of any 
histologic subtype, clinically stage I-II planned for primary surgery. 
-Women with at least one of the following preoperative high risk criteria 
(endometrioid cancer FIGO grade III, a non endometrioid histology, 
>=50% myometrial tumor invasion, cervical stromal invasion or until 
February 14 2017 a non-diploid cytometry).  
-Women must be able to understand and sign an informed consent in 
Swedish language.  
-Absence of any exclusion criteria. 
Exclusion criteria 
( none fulfilled) 
-Non-consenting patients.  
-Pregnancy 
-Inability to understand written and/or oral study information.  
-WHO performance status III or more. 
-Age > 85 years and WHO performance status II or more.   
-Surgical contraindication to a laparoscopic approach or 
lymphadenectomy at surgeon’s discretion. 
-Anesthesiologic contraindication to a laparoscopic approach at the 
anesthetist’s discretion.  

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-Preexisting lower limb lymphedema grade II or more. 
-Locally advanced disease or intraabdominal/distant metastases at 
preoperative CT, MRI or ultrasonography.  
-Allergy to Iodine. 
-Patients with a known liver disease. 
-Patients with a bleeding disorder or mandatory antithrombotic 
treatment. 
Primary outcome 
The sensitivity of the sentinel lymph node specimen in women with 
nodes mapped by ICG. The negative predictive value of the sentinel 
lymph node concept in women who are mapped 
Secondary outcome 
Bilateral and unilateral detection rate.  
Sensitivity of the overall SLN concept (Defined by ICG and/or SLN 
Macro) 
Intraoperative complications (SLN procedure as such and per sub-
procedure) 
Postoperative complications until 30 days after surgery 
Standard treatment 
Hysterectomy, BSO, pelvic and paraaortic lymphadenectomy and 
infracolic omentectomy as per national guidelines  
Experimental 
treatment 
Separate removal of sentinel lymph nodes and upper paracervical tissue 
before standard treatment as of above. 
Duration of study 
3-7 years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. Background  

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3.1 Endometrial cancer and surgical staging 
 
Minimally invasive surgery confers similar survival with lower health care costs and less 
perioperative complications than laparotomy in the treatment of endometrial cancer (EC)  
MIS is the recommended treatment modality with robot-assisted laparoscopic surgery 
gaining ground over traditional laparoscopy (1-4).  
In endometrial cancer, nodal involvement is a strong prognostic factor and also determines 
the addition of adjuvant treatment.  Therefore, information on nodal metastases is important 
and in many countries a full pelvic and paraaortic lymphadenectomy is recommended 
despite an increased risk for lymphatic complications in form of lymphedema, lymphocysts 
and in rare cases lymphatic ascites (ESMO-ESGO-ESTRO, Swedish National Treatment 
protocol, NVP 2012).  
 
 
3.2 The sentinel node biopsy concept in endometrial cancer 
 
Preliminary data from the department of Obstetrics and Gynecology in Lund shows that 
robot assisted surgery with detection of sentinel lymph nodes with the use of ICG is feasible 
in 84% of unselected endometrial cancer patients selected for primary surgery using the 
inclusion criteria in this study.  
The concept of identifying nodal metastases by detection of sentinel lymph nodes as a 
marker of nodal metastatic disease or not therefore is appealing. However, during later 
years many studies have been published, most of them retrospective, using a variety of 
tracers and with little or no information on used surgical algorithm, used definition of SLN 
and without reference to lymphatic anatomy.   
 
The bilateral technical success rate of SLN identification is important to determine if this 
technique can be translated to clinical practice. A clear anatomically definition of what is a 
SLN and a strict surgical algorithm as described in this study is important. Based on pilot 
studies at our institution on cervical and endometrial cancer we expect that the bilateral 
pelvic SLN identification (defined as at least one SLN per hemi pelvis) will be 90% or 
more. We intend to separately study if reinjection of ICG will enhance the bilateral 
detection rate. A lower bilateral detection rate will lead to the need of full 
lymphadenectomy in a higher proportion of patients. In the present study, including only 
high risk endometrial cancer patients, this has no overall clinical significance as a complete 
lymphadenectomy is the alternative for this group of patients. A lower than expected 
detection rate will therefore not be an incentive for premature stop of accrual.  
Importantly, accreditation of surgeons will be performed as described and is likely 
important to achieve a similar success rate as in pilot studies. 
 
 

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4. Rationale for study 
Technical success rate/ SLN mapping rate varies. A high technical success rate is crucial to 
avoid the need for a full hemi-pelvic or pathway-wise LND in case of failure. In pilot 
studies from Lund University we have shown that reinjection of tracer increases the 
technical success rates both defined per hemi-pelvis and pathway-wise, defined by 
detection of at least one SLN per hemi-pelvis to at least 90%. By the use of Indocyanine 
green, a fluorescent tracer, we have also identified two bilateral separate pelvic pathways, 
the upper para-cervical pathway (UPP) running along the upper lympho-vascular  
parametrium usually to  external iliac and/ or obturator nodes and the further lateral to the 
common iliac artery to paraaortic nodes and the lower para-cervical pathway (LPP) running 
via the sacro-uterine ligament to nodes medial of the internal iliac artery and/ or presacral 
nodes then further medial to the common iliac artery to paraaortic nodes. Hence there are 
two bilateral pelvic pathways draining further to the paraaortic region below as well as 
above the inferior mesenteric artery (appendix 1). Therefore, we believe that lower 
paraaortic SLN can only be defined in the absence of pelvic SLN along the pelvic  
pathways but with clear filling of pelvic lymphatic channels up to the aorta. In pilot studies 
at our institution we have never observed this situation. Alternatively, lymph nodes cranial 
of the inferior mesenteric artery but caudal of the left renal vein (infrarenal, supra-
mesenteric nodes) theoretically may be dyed via the infundibulo-pelvic ligament and may 
then be considered as true paraaortic SLN but only in the absence of dyed node more 
caudally. Neither this situation has been observed after a cervical injection of tracer rarely 
filling the infundibulo-pelvic ligament. Moreover, attempts to find paraaortic SLN would be 
a step away from decreasing surgery in endometrial cancer.  Although detection of pelvic 
SLN may miss paraaortic skip metastases we hypothesize that ultra-sectioning of SLN and 
including a pre-sacral dissection of SLN may decrease the incidence of true paraaortic skip 
metastases.  
Surgical competence and experience is necessary to achieve a high technical success rate 
and a low false negative rate for SLN. The study setting including only high volume 
surgeons at two tertiary high volume centers enables an evaluation of the true potential of 
the pelvic SLN concept in endometrial cancer.  This study aims to include consecutive 
high-risk endometrial cancer patients fulfilling criteria to ensure the results are 
representative for the endometrial cancer population.  
 
For site accreditation and surgeons’ eligibility, see section 7.5 
 
 
 
 
 
5. Study objective 

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5.1 Primary objective 
This study aims to evaluate sensitivity and false negative rates of the pelvic sentinel node 
concept based on a defined surgical algorithm and with a clear definition of SLN based on 
described uterine lymphatic anatomy with the use of ICG as tracer. 
 
5.2 Secondary objectives 
To evaluate the overall SLN concept based on SLN identification by ICG and intraoperative 
find of macroscopically cancer suspect nodes.  
To evaluate if reinjection of tracer increases the bilateral technical success rate. 
To evaluate perioperative outcomes, adverse events, postoperative complications and the 
occurrence of  “isolated” paraaortic lymph node metastases when pelvic sentinel lymph 
node mapping is performed.  
 
6. Study plan and design 
Prospective non-randomized controlled trial, where every included woman is her own 
control. 
 
Overview study plan. 
 
 
Consecutive high risk endometrial cancer planned for robotic surgery, clinically with the 
primary tumor confined to the uterus (uterine stage I-II).  
High risk defined as at least either of deep (>=50%) myometrial invasion, cervical stromal 
invasion, endometrioid cancer FIGO grade 3, or a non-endometrioid histology or until 
February 14, 2017 a non-diploid tumor. 
 
 
 
 
 
                                                      Cervical injection of ICG 
 
 
 
 
Registration of adverse events during insufflation and placement of port including 
necessary adhesiolysis.  
 
 

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Pelvic SLN identification with near infrared technique for identification of Indocyanine 
green (ICG) in lymphatics and lymph nodes. Ipsilateral cervical reinjection of ICG in case 
of non-display of any lymphatic pathway. Separate removal of the upper lymphovascular 
parametria. Registration of SLN- associated intraoperative adverse events. 
 
 
 
 
 
Surgery according to the preoperative assignment:  
A= primarily a full pelvic and paraaortic lymphadenectomy to the level of the left renal vein 
after detection of pelvic SLN  
B= Due to comorbidity secondly a full pelvic lymphadenectomy after detection of SLN.  
Omentectomy in non-endometrioid cancers. Registration of associated intraoperative 
adverse events. 
 
 
 
 
A Querleu-Morrow Type A to C1 hysterectomy and bilateral adnexectomy. Registration of 
associated intraoperative adverse events. 
 
 
SLN’s for ultrasectioning and immunohistochemistry. The remaining nodes 
for standard pathological bisectioning and staining with hematoxylin/Eosine.   
    
                                                                              
                                                                               
 
 
Registration of postoperative adverse events until 30 days after surgery using the Clavien 
Dindo classification. 
 
                                               
 
Continuous data management. Interim analysis of sensitivity and false negative rates for 
SLN’s after 50 ICG mapped pelvic node positive patients (see section 11). 
 
 

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7. Study treatment 
 
7.1 Overview treatment 
 
• Intraoperative cervical injection of ICG (immediately before onset of surgery)  
 
• Intraoperative lymphatic mapping and sentinel node identification with robotic Near 
Infrared fluorescence imager will be used for an initial transperitoneal, then 
retroperitoneal evaluation of display of ICG fluorescence. The retroperitoneal 
dissection with opening of the avascular planes saving the lymphatic vessels will 
start pre-sacrally then further with the pelvic side walls. The upper lympho-vascular 
parametria will be kept intact by a careful opening of the para-rectal and para-
vesical spaces.   
• An ipsilateral reinjection of ICG will be performed in case of non-display of either 
of UPP or LPP. If the sentinel node cannot be identified in a particular pathway 
following a minimum of 10 minutes search, the case should be described as a ICG-
negative mapping event for that pathway.  
• The results of the lymphatic mapping will be marked on the anatomic plan and the 
specimens and labeling of those will be according to descriptions above. 
• The complete SLN algorithm should be adhered to, i.e. in case of a ICG negative 
mapping (for SLN type 1 and 2) any macroscopic nodes suspicious for metastases 
should be removed and regard as SLN macro. All patients will be subject for at 
least a full pelvic lymphadenectomy after removal of SLN. 
• The upper lympho-vascular parametrial tissue (the tissue medial of the obliterated 
umbilical artery, with the supra-vesical artery as distal/ventral border, the ureter as 
dorsal border and including tissue adjacent to the inner side of the broad ligament) 
will be removed and evaluated the same way as SLN’s. This is to investigate the 
presence of lymph node in the upper parametria, theoretically the most juxtauterine 
nodes, hence the SLN. A separate dissection of potential nodes in the parametrial 
tissue is often difficult as most of the tissue is ICG positive. 
• A full pelvic and paraaortic lymphadenectomy will be performed after identification 
of SLN’s. To evaluate a potential occurrence of paraaortic SLN the infrarenal 
paraaortic lymphadenectomy will be performed with regards to definitions of 
potential paraaortic SLN’s as of above. 
 

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• A Querleu-Morrow type B1 or C1 hysterectomy as appropriate with primarily a 
paraaortic lymphadenectomy to the level of the left renal vein or a full pelvic 
lymphadenectomy.  
• All SLN and the upper parametrial tissue will be subject for ultra-sectioning and 
Immunohistochemistry at the histopathologic evaluation.  
 
• Frozen section of the SLN will not be performed.  
 
• Complications will be recorded and to enable association with parts of the 
procedure, most importantly, the SLN procedure as such and the lymphadenectomy, 
will be subdivided as described above. The classification described under the 
adverse events tables will be used. 
 
• NOTE: Site accreditation and surgeon’s skill and adherence to protocol will be 
verified as described. See section 7.5. 
 
 
7.2 Standard treatment 
 
7.2.1 Surgical Procedures 
• Patients with endometrial cancer presumably stage I will undergo detection of pelvic 
SLN with fluorescent technique followed by a pelvic and paraaortic 
lymphadenectomy to the level of the left renal vein. A Querleu-Morrow type B1-CI  
hysterectomy with a bilateral salpingoophorectomy will be performed. An infracolic 
omentectomy will be performed in women with a non-endometrioid histology.  
• Robot-assisted laparoscopy will be used. 
 
7.2.2 Definition of anatomical boundaries for pelvic and paraaortic lymphadenectomy 
 
Anatomical boundaries of lymph node compartments in the female pelvis 
 
Lymph node 
compartment 
Cephalad limit Lateral limit 
Caudad limit 
Medial limit 
External iliac 
area 
Bifurcation of 
external and 
internal iliac 
artery 
Genitofemoral 
nerve 
Cloquet’s 
lymph node 
External iliac 
vein 
Obturator 
fossa 
Internal iliac 
vein 
Ileopsoas 
muscle 
Os pubis, 
obturator nerve 
Obliterated 
umbilical artery 

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Common iliac  
Aortic 
bifurcation 
Genitofemoral 
nerve 
Bifurcation of 
external and 
internal iliac 
artery 
Common iliac 
artery 
Presacral 
Aortic 
bifurcation 
Common iliac 
artery 
Lower 
promontory 
Hypogastric 
nerve (as 
distinction 
between right 
and left) 
Lower 
paraaortic 
Inferior 
mesenteric 
artery 
Ureter 
Aortic 
bifurcation 
 
Higher 
paraaortic 
Left renal vein 
Ureter 
Inferior 
mesenteric 
artery 
 
 
 
 
7.3 Intervention 
 
7.3.1 Indocyanine green, dilution, dose and injection 
 
7.3.1.1 Drug Information 
Indocyanine Green solution (ICG) 2.5mg/mL. 
Description: ICG (Pulsion medical system, PICG0025SE, Feldkirchen Germany) is a 
sterile, lyophilized green powder containing 25 mg of Indocyanine green with no more than 
5% Sodium Iodide.  
The ICG solution is prepared immediately before surgery and intended for single patient 
use. For preparation, 10mL of sterile water is injected directly into the lyophilized ICG in 
its glass vial. Invert the vial multiple times to ensure thorough mixing. Draw up 0,25 mL in 
six 1 mL syringes from the vial with ICG solution (2,5mg/mL) for the cervical injection. A 
0.6x38mm 23Gx1 ½ needle. The content of four of the syringes are used for the initial 
injection and in case of non-display of any pathway one or two of the other are used for an 
ipsilateral re-injection.  
The ICG solution is stored at room temperature. The solution is active for 6 hours, and 
should be discarded after that period of time. 
Manufacturer: Pulsion medical system, Feldkirchen Germany 
Availability: ICG will be provided by the manufacturer to each site. 
 
 

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Adverse Effects if ICG: All adverse effects are allergic in nature and occur in <1% of 
patients. Anaphylactic or urticarial reactions have been reported in patients with or without 
a history of allergy to iodides. If such reactions occur, treatment with the appropriate agents 
(e.g. adrenalin, antihistamines, corticosteroids) should be initiated. 
Contraindications: Known hypersensitivity to iodine containing compounds. Known liver 
failure. Radioactive iodine uptake studies should not be performed for at least 1 week 
following the use of ICG. 
 
Please refer to the current ICG package insert for complete prescribing information 
 
7.3.1.2 Injection of Indocyanine Green (ICG) 
• The ICG is prepared by thorough mixing of 10mL of sterile water with the 
lyophilized ICG in its vial creating a 2.5mg/mL concentration. The lot number, 
expiration date and dose injected (mg) will be recorded. 
• Six separate sterile 1mL syringes is prepared with 0.25 mL ICG solution (0.625 mg 
ICG) in each syringe is prepared. 
• A 0.6x38 mm 23G needle is attached to each syringe for the injection. A separate 
back table is used for the syringes. 
• The ICG injection will be performed immediately before placement of surgical port 
and docking the robot. 
• Half the ICG volume in each syringe is injected sub-mucosally and half the volume 
3 cm into the cervical stroma at 2-4-8-and 10 O’clock respectively to a total dose of 
2.5mg ICG and a total volume of 1 mL. Time for injection is recorded. 
• After injection of dye, a fornix presenter without an intracervical device is placed 
• A second ipsilateral injection of 0,25mL ICG is performed in case of non-display of 
either of the upper (UPP) or lower (LPP) paracervical pathways after a minimum of 
10 minutes’ observation time after ICG injection. The injection is done at 3 and 9 
O’clock respectively, half the volume submucosally and half the volume 3 cm into 
the cervix.   
• Display of the separate lymphatic pathways (UPP, LPP and IPP will be recorded 
after the first and if performed after the second injection). 
 
7.3.2 Sentinel Node Identification 
• Dissection for detection of SLN’s will start with the cranially with pre-sacral area  
(along the LPP) to prevent disturbance from leaking ICG, thereafter, following 
opening of the avascular paravesical and pararectal planes to isolate the upper 
paracervical pathway. 
• The described procedures in this protocol will be performed with robot-assisted 
laparoscopy. 
 

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The sentinel nodes are defined as the juxtauterine ICG positive node with an afferent ICG 
positive lymphatics in each of the UPP and LPP respectively on each pelvic side with the 
potential of parallel lymphatics in the UPP to the external and obturator areas. These SLN 
are defined as SLN type 1.  
In case of a ICG positive lymph vessel where no nodes are ICG positive in that pathway, 
the node where the ICG positive lymphatic channel ends is defined as SLN type 2.  
Nodes macroscopically suspect of metastatic disease will be defined as SLN Macro 
regardless of ICG uptake but be defined as ICG positive or negative as appropriate. 
Importantly, to secure accuracy, the positions and types of SLN will be marked on an 
anatomical chart, recorded on a list with anatomical locations and placed in pre-labeled jars 
with corresponding anatomical positions and numbers. This list is used by the department 
of pathology for reporting the results to minimize the risk of errors in location of nodes and 
which nodes are SLN’s and non-SLN’s. A copy of the list is kept in the patients study file. 
Nodes defined as SLN will have red labels on the jars, other nodes will have black labels. 
(Appendix 2) 
SLN’s will be sent for final histological evaluation including ultrasectioning and 
immunohistochemistry as described. SLN’s will not be sent for frozen section unless 
clinically motivated. 
 
For the pelvic SLN concept, ideally one SLN should be identified per LPP and UPP per 
pelvic side wall. 
 
 
The display of ICG in the respective pathways will be evaluated a minimum 10 minutes 
after the injection of ICG, first transperitoneally, and if not seen, after opening of the 
retroperitoneal avascular planes starting with the presacral plane, then the paravesical and 
pararectal planes leaving the lymphatics intact with the aid of switching between white light 
and the ICG mode (Firefly mode). In case of non-display of a pathway an ipsilateral 
injection of ICG as described will be performed. Another 10 minutes will be allowed for 
awaiting distribution of ICG in the respective pathways. To minimize disturbance by 
leaking ICG identification and removal of SLN’s starts cranially, presacrally (along the 
LPP) and continues at the pelvic side walls along the UPP. After removal of SLN’s the 
upper lymphovascular parametrial tissue is removed separately (defined as the tissue along 
the uterine artery, medial to the obliterated umbilical artery and caudal of the supravesical 
artery) as it may contain lymph nodes that may not be separated from the green 
lymphovascular tissue and hence be the juxtauterine lymph node.  
After removal of sentinel nodes, a complete compartment-wise pelvic and paraaortic 
lymphadenectomy is performed followed by the hysterectomy.  
 
 
 

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7.3.2.1 Identification and definition of potential paraaortic SLN’s. 
 
During the paraaortic lymphadenectomy, situations where paraarotic SLN’s theroretically 
can be defined are looked for. These situations are: 
1. ICG positive supramesenteric lymph nodes without ICG positive nodes in the 
inframesenteric area, i.e nodes dyed directly and solely via lymphatics in the 
infundibulopelvic ligament.  
2. In case no pelvic SLN’s are identified and inframesenteric ICG positive nodes are present 
the most caudal of the inframesenteric ICG positive nodes on the right and left side will be 
considered paraaortic SLN’s. See Appendix 2. Anatomic plan for localization of sentinel 
lymph nodes. 
 
 
 
7.4 Treatment modifications 
 
In case of no ICG uptake (including reinjection according to protocol) the SLN algorithm 
should be followed, i.e. removal of any macroscopically suspect nodes (marked as SLN 
macro) and as planned a full compartment-wise lymphadenectomy. 
As the national protocol for high risk endometrial cancer recommends a full paraaortic and 
pelvic lymphadenectomy no patient will be subject for lymphadenectomy beyond the 
guidelines. 
 
In case of conversion to open surgery before identification and removal of SLN’s the 
patients should be included in evaluation of adverse events and feasibility on an intention to 
treat basis but not included in the calculation of sensitivity and negative predictive values 
for the sentinel node concept. 
 
 
 
 
7.5 Participating surgeons 
All included surgeons outside the primary investigating center must have had a case 
observation at the primary investigating center followed by an approved site visit by the 
principal investigating surgeon at their home center ensuring adherence to protocol.  All 
included surgeons at the primary investigating center were approved by the principal 
investigating surgeon.  
All included surgeons must have a previous experience of at least 100 robot assisted 
procedures. 

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8. Evaluation of histopathology 
 
8. 1 Histopathologic evaluation of the sentinel nodes  
All macroscopically identified SLN lymphoid tissue will be embedded and bisected if the 
minimum thickness exceeded 3 mm. If no macroscopically lymphoid tissue is identified in 
SLN or parametrial tissue the most suspicious find will be embedded and microscopically 
investigated. Ultrastaging using hematoxylin/ Eosin staining will be performed in five 
sections at three different levels, separated by 200 µm, if the maximum diameter of the 
SLN tissue exceeds one mm. From first and second level immunohistochemistry (pan-
cytokeratin, MNF 116) will be performed. If no macroscopically lymphoid tissue is 
identified in SLN or parametrial tissue the most suspicious find will be embedded and 
microscopically investigated. ITC can be detected by Hematoxylin/Eosin or by 
Immunohistochemistry alone. 
 
8.1.2 Classification of tumor size in SLN’s 
Sentinel nodes will be classified according to a modification of the AJCC staging for 
axillary nodes from breast cancer as follows: 
Macro metastases = tumor greater than 2.0 mm in diameter. 
Micro metastases = tumor cell aggregates between 0.2 and 2.0 mm in diameter. 
Isolated tumor cells =individual tumor cells or aggregates that are less than 0.2mm in 
diameter, usually detected by immunohistochemistry. 
Tumor absent – no tumor cells identified in H&E (or immunohistochemically, if applicable) 
stained sections. 
 
 
8.2 Histopathologic evaluation of the non-sentinel nodes 
Non- SLN nodes less than 3 mm in thickness will be embedded whole, and from nodes 
thicker than 3 mm at least half the node will be embedded. The slides will be evaluated 
after hematoxylin/Eosin staining. 
 
Non-sentinel lymph nodes will be reported as positive or negative for metastases based 
upon routine sectioning and examination of a single H&E stained section. 
 
 
 
9. Outcomes 
 

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9.1 Primary outcome 
The sensitivity, negative predictive value  and false negative rates of the sentinel lymph 
node procedure in women with SLN nodes mapped by ICG in at least one SLN (per patient 
analysis). 
 
9.2 Secondary outcome 
The sensitivity, negative predictive value and false negative rates of the sentinel lymph 
node concept in women SLN mapped by ICG and /or defined as SLN macro (the overall 
SLN concept, per patient analysis) 
Sensitivity of SLN defined by ICG per lymphatic pathway. 
Bilateral and unilateral detection rate including reinjection of ICG. 
Intraoperative complications. 
Postoperative complications until and including 30 postoperative days. 
The occurrence of paraaortic skip metastases 
 
 
10. Patient enrollment 
Consecutive women with high risk endometrial cancer will be screened for eligibility. Both 
participating sites are tertiary referral centers within a public health care system.  
 
10.1 Inclusion criteria 
• Women of age 18 years and older at the time of informed consent. 
• Women with a pathologically proven endometrial carcinoma of any histologic 
subtype, clinically stage I-II planned for primary surgery 
• Women with at least one of the following preoperative high risk criteria 
(endometrioid cancer FIGO grade III, a non endometrioid histology, >=50% 
myometrial tumor invasion, cervical stromal invasion or until February 14 2017 a 
non-diploid cytometry)  
• Women must be able to understand and sign an informed consent in Swedish 
language.  
• Absence of any exclusion criteria 
 
10.2 Exclusion criteria 
• Non-consenting patients 
• Pregnancy 
• Inability to understand written and/or oral study information  
• Who performance status III or more 
• Age > 85 years and WHO performance status II or more   
• Preexisting lower limb lymphedema grade II or more  

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• Surgical contraindication to a laparoscopic approach or lymphadenectomy at 
surgeon’s discretion. 
• Contraindication to a laparoscopic  procedure at the anesthetist’s discretion  
• Locally advanced disease or intraabdominal/distant metastases at preoperative CT, 
MRI or ultrasonography  
• Allergy to Iodine  
• Patients with a known liver disease 
• Patients with a bleeding disorder or mandatory antithrombotic treatment.  

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10.3 Schedule of events table/ checklist 
 
 
  
 
 
 
 
 
 
 
Procedures 
      Screening 
   Enrollment/ 
      Baseline 
Surgery-ICG 
SN/postoperati
ve parameters 
  
Final histology 
Lgll/inner gen. 
4 weeks postop 
Medical History 
routine 
X 
 
 
 
Gynecologic History 
routine 
X 
 
 
 
Physical Exam 
routine 
X 
 
 
 
CT abdomen/chest 
evaluation 
X 
 
 
 
MRI/US evaluation 
X 
 
 
 
“High risk 
endometrial cancer” 
X 
 
 
 
Informed consent 
oral 
 
X 
 
 
Informed consent 
written 
 
X 
 
 
Enrollment 
 
X 
 
 
Preop CRF 
 
X 
 
 
Surgery with ICG 
 
 
X 
 
 
Perop CRF 
 
 
X 
 
Specimens from 
surgery sent and 
answered by 
pathologist as per 
protocol 
 
 
X 
 
 
X 
 
Postop 
CRF/including 30 day 
morbidity 
 
 
X 
 
X 

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11.  Evaluation criteria 
 
 
o Patients with at least one SLN identified will be included for determining the sensitivity and the 
negative predictive value of the SLN ICG concept (SLN type 1-2)  and the overall SLN concept 
(type 1-2 and macro)  
 
o All patients who are injected with ICG and not converted to open surgery before detection and 
removal of SLN’s will be included for evaluation of technical success rate (described per patient, 
per hemi pelvis and per separate pathway) after first and in case of non-display of any of the LPP 
and UPP after reinjection of ICG as described.  
 
o All patients included, regardless of conversion to open surgery and mapping of ICG will be 
included in the overall evaluation of feasibility and safety. 
 
o Intraoperative adverse associated with the detection and removal of SLN will be evaluated and 
reported separately  as well as adverse events related other sub procedures during the operation on 
all patients who have at least one SLN removed regardless of type, i.e all patients in whom SLN 
were removed separately. 
 
o Postoperative complications until 30 days after surgery will be reported using the Clavien Dindo 
classification.  
 
 
12. Adverse events 
 
The study protocol has been revised related principles for study monitoring and for reporting 
adverse events to the principal investigating centre after inclusion of the second centre.  
 
12. 1 Definitions 
 
An adverse event (AE) is any new medical problem or exacerbation of an existing problem 
experienced by a subject enrolled in the study, whether or not it is considered drug-related by the 
investigator. (Appendix 3) 
 
This study will utilize the Adverse Events Logs (Tables 10.1-5). Any SAE will be reported to the 
study coordinator (Michele.bollino@med.lu.se) using the SAE log. (appendix 4).  
 
 
 

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Adverse events related to the study drug (ICG). 
All adverse events occurring from the first dose of study drug until hospital discharge (whether or 
not attributed to the study drug) will be reported on the Adverse Event Log. In addition, any 
adverse event reported by the subject to the investigator after discharge and determined to be 
reasonably associated with the study drug should also be captured and followed until resolution. 
 
Adverse events related to the sentinel node procedure as such (excluding AE related the study 
drug, ICG)  
All intraoperative events related to the SLN procedure will be reported on the adverse events log.  
 
Adverse events related the surgical procedure (excluding the SLN part) including AE until 30 
postoperative days. 
All adverse events will be reported on the adverse events log. 
 
Serious adverse event (SAE):  
An adverse event that results in one or more of the following: 
-Any death occurring until and including 30 postoperative days  
-Any life-threatening event until and including 30 postoperative days. 
-Any medical event requiring inpatient hospitalization or prolongation of existing hospitalization 
beyond five postoperative days  
 
NOTE: Hospitalizations that are not considered SAE are: 
-Hospitalization planned prior to first administration of study drug 
-Hospitalization for elective treatment of a pre-existing condition unrelated to the study medication  
- Hospitalization due to social / practical reasons such as an untimely coordination with local 
community home care services.  
 
Attribution: Attribution is the determination of whether an adverse event is related to a medical 
treatment or procedure. The categories of attribution are: 
 
Definite: The adverse event is clearly related to the study drug/intervention  
Probable: The adverse event is likely related to the study drug/intervention. 
Possible: The adverse event may be related to the study drug/ intervention 
Unlikely: The adverse event is doubtfully related to the study drug/ intervention 
Unrelated: The adverse event is clearly NOT related to the study drug/intervention 
 
 
Unexpected Adverse Event: An unexpected adverse event is an event not mentioned in the 
package insert/ manufacturer’s instructions or the specificity or severity of which is not consistent 
with the package insert/ manufacturer’s instructions. 
The grading described beneath and the attribution described above will be used for cathegorization 
of unexpected adverse events. 

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Reporting to the IRB: 
Each participating center will report adverse events to their IRB per local guidelines.  
 
Coordinating Center Reporting Responsibilities 
 
Reporting to the study coordinator, Lund University Hospital 
Same criteria as above. 
 
Reporting to the IRB: 
Same criteria as above. 
 
The Study Coordinator will distribute reports which are serious, unexpected and associated with 
the study intervention (possibly, probably or definitely) to all participating investigators. Copies of 
all serious adverse event reports will be kept on file the department of Obstetrics and Gynecology, 
Lund University Hospital. 
 
The study coordinator will also report all individual SAE’s related to study drug, the sentinel node 
procedure as such, are life threatening or resulting in death (defined above and in table 10.6) to the 
Safety Monitoring Committee (SMC) for clinical studies at  the respective hospital (Skåne 
University Hospital and Karolinska University Hospital)  for an independent evaluation.  
 
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks (or 
benefits) to the patient warrant early closure of the study, this recommendation should be made in 
writing to the SMC.  Alternatively, the SMC may initiate suspension or early closure of the study 
based on its review of the investigator reports. 
 
13. Study Monitoring / study accrual oversight 
 
The study principal investigator, local principal investigator and study coordinator will conduct 
meetings (teleconferenced) every 6 months to discuss the protocol. The s-PI and l-PI can call a 
meeting to convene at additional times if deemed necessary, for example following statistical 
review at the interim period if stopping the study for either achieved goals or futility. Apart from 
the monitoring described below, the number of node positive patients and potential false negative 
SLN’s will be monitored continuously by e-mail to the study coordinator by the use of the study 
number assigned to each patient.  
 
In case of identified inconsistencies or missing data, additional source documents (identified only 
by unique patient number) will be requested from the site to resolve ongoing inconsistencies. 
 
The principal investigator and/or the study coordinator will, if deemed necessary by the principal or 
second participating center perform audits of informed consents and subject eligibility. 

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13.2 Duration of study 
The study was initiated at Lund university hospital (From June 2014) with a later inclusion of the 
second investigating center (Karolinska University Hospital, from February 2017) motivating a 
revision of the study protocol related estimated time for enrollment of patients and for accreditation 
of the second centre and its surgeons. 
 
Assuming that the prevalence of lymph node metastases is 20% in high risk endometrial as defined 
above 250 patients will be needed to obtain 50 lymph node positive observations. Given a 95% 
bilateral detection rate of ICG positive SLN’s approximately 15 patients more will need to be 
included. On the other hand, ultrasectioning and IHC of SLN’s may increase the proportion of 
patients with nodal metastases by identifying micro metastases. As there will be a continuous 
report of ICG mapped pelvic node positive patients to the study coordinator an interim analysis will 
start after 50 such patients regardless of the total number of patients included (see 11, statistical 
considerations).  Accrual will not be suspended during the interim analysis as the intervention is 
estimated to pose minimal risk to patients and the national treatment protocol, recommending a full 
lymphadenectomy, will be followed, even in the event of futility. 
If the trial continues to stage 2, another 300 patients will be required. (see 15, statistical 
considerations) 
Given an estimate that the accrual rate is five high risk patients per month per center (each of Lund 
University Hospital and Karolinska University Hospital) and the fact that the second center started 
inclusion later, a total of 46 months (calculated from June 2014) will be required to reach 250 high 
risk endometrial cancer and a total of 30 additional months to reach 550 high risk patients. 
 
14. Data Management 
Preoperative, intraoperative and postoperative data from each surgery will be recorded on 
standardized study sheets available to each study site. Each study site will be allocated a study 
number which will serve as the prefix to the case number. For example, Lund university Hospital 
will be allocated the prefix “Lu” and the first study patient will have the study number “Lu-001. 
Each investigating center will hold a record with the full identification of patients whereas data 
otherwise should only identify the patient by the study number (see above). 
Staff at the individual centers will be responsible for completing the data collection sheet for each 
patient and all data will continuously and all be entered into a common secured web-based database 
(https://data.dynareg.se/slnicgec)  using the designated study numbers.  Upon interim analysis, the 
full data will be monitored by the study coordinator, the principal investigator, local principal 
investigator and study statistician.  
Separate analysis of patient data from individual sites can only be performed with the written 
permission of the study principal investigator (Jan Persson). 
 
 
 

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14.1 Early Study Closure 
Death will be reported according to section 10.1 above and per local IRB reporting guidelines. The 
SMC will review all reported deaths monthly. Early closure of the study will be based on 
judgement of the SMC. 
The study will be stopped for futility reasons as described under the statistics section. 
 
14.2 Protocol Deviations 
Major protocol deviations shall be reported by mail to the study coordinator. 
Michele.bollino@med.lu.se and filed at Lund University Hospital using the designated study 
number. Major protocol deviations include, but are not limited to, violations to inclusion/ exclusion 
criteria, erroneous preparation of ICG or surgery by a non-accredited surgeon.  
 
 
15. Statistical considerations 
This study is designed to evaluate the application of the sentinel node (SLN) technique in 
determining the lymph node (LN) status in patients with high risk endometrial cancer 
The main statistical endpoint will be sensitivity and false negative rates /negative predictive value. 
The sensitivity is the proportion of patients who test as SN (+) among the patients who have LN 
metastases (LN+). The patients will, according to the Swedish national guidelines for high risk 
endometrial cancer undergo a full infrarenal paraaortic and pelvic lymphadenectomy, however with 
separate removal of SLN as defined above, hence serve as their own controls. As lymph node 
status (lymph node metastases or no lymph node metastases) is a definite parameter (false positive 
result can by definition not occur) specificity and positive predictive values will not be reported in 
this study. 
The final sample size analysis was performed after one year inclusion of patients as the bilateral 
detection rate of SLN (including reinjection of ICG if necessary) initially was not known. The time 
for accrual was revised after inclusion of the second participating center. 
 
We used the Fleming two stage design for evaluation of study termination (Fleming, 1982). 
The null hypothesis that the sensitivity is 85% will be tested against one-sided alternative.  
The study is terminated after stage one if it is unlikely that the sensitivity is ≥ 92.5% or if 
sensitivity is significantly higher than 85%. In the first stage, 50 LN+ patients with at least one 
pelvic SLN defined by ICG will be accrued. If there are 43 or fewer responses in these 50 patients, 
the study will be stopped for futility. If there are at least 48 responses in 50 patients, the study will 
be stopped and the null hypothesis rejected. Otherwise, 69 additional patients will be accrued for a 
total of 119 node positive patients. The null hypothesis will be rejected if 108 or more responses 
are observed in 119 patients. This design yields a type I error rate of 0.05 and power of 0.8 when 
the true sensitivity is 92.5%. 
For the first stage, we estimated a total of 250 patients to be included taking into consideration a 
95% bilateral SLN detection rate, and an estimated 23 % rate of node positivity including an 
increase in node positivity rates due to ultra-sectioning and immunohistochemistry. For the second 

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stage, another 300 patients have to be included. As the number of node positive patients will be 
reported continuously to the study coordinator this will be decisive of the number of patients that 
has to be included for each stage.  
 
 
 
16. Ethical considerations 
 
16.1 Informed consent 
Before inclusion in the study, patients will be given oral and written information in Swedish of the 
study aims, all treatment procedures and expected and possible adverse events see. They will be 
informed as to the strict confidentiality of their patient data, and that their medical records will be 
reviewed by their treating physician and personnel only. The patient is at any time, with or without 
given reason to do so, free to withdraw their consent to study participation, and this choice will not 
affect their subsequent treatment options or care.  A copy of the signed informed consent will kept 
in the study file. 
 
16.2 Patient protection and Good Clinical Practice 
The responsible investigator will ensure that the study is conducted in agreement with the 
declaration of Helsinki and/or Swedish laws and regulations; whichever provides the greatest 
protection for the patient. Participating women will be treated according to the international 
guidelines on GCP 
 
16.3 Subject identification 
Participating patients will be identified by a study specific code consisting of the patient’s initials 
and the investigating site, followed by a three-digit number. This code will be used when transfer 
of data into the study database. The woman’s national identification number will not be entered 
into the database. The key to the code will be available to the investigator only. 
 
17. Trial sponsor and financing 
This is an academic study sponsored by the investigator, Skåne County Council, Skåne University 
Hospital Donations fund, Sweden, and Radiumhemmets Research funds, Sweden, with no 
involvement of any external sponsor. 
 
18. Publications 
All study data belong to the investigators. It is the intention to publish the results in a scientific 
journal. Co-authorship and the listing of authors’ names are determined by the investigators. 
 
 
 

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19. Approvals 
The study, patient information and informed consent must be approved by each participating site’s 
regional ethics committee before any patients are enrolled.  
 
 
20. References/Bibliography 
 
1. Walker JL, Piedmonte MR, Spirtos NM, Eisenkop SM, Schlaerth JB, Mannel RS, Spiegel G, 
Barakat R, Pearl ML, Sharma SK. Laparoscopy compared with laparotomy for comprehensive 
surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. 
J Clin Oncol. 2009 Nov 10;27(32):5331-6. doi: 10.1200/JCO.2009.22.3248. Epub 2009 Oct 5. 
 
2. Janda M, Gebski V, Brand A, Hogg R, Jobling TW, Land R, Manolitsas T, McCartney A, 
Nascimento M, Neesham D, Nicklin JL, Oehler MK, Otton G, Perrin L, Salfinger S, Hammond I, 
Leung Y, Walsh T, Sykes P, Ngan H, Garrett A, Laney M, Ng TY, Tam K, Chan K, Wrede CD, 
Pather S, Simcock B, Farrell R, Obermair A. 
Quality of life after total laparoscopic hysterectomy versus total abdominal hysterectomy for stage 
I endometrial cancer (LACE): a randomised trial. 
Lancet Oncol. 2010 Aug;11(8):772-80. doi: 10.1016/S1470-2045(10)70145-5. Epub 2010 Jul 16. 
 
3. Walker JL, Piedmonte MR, Spirtos NM, Eisenkop SM, Schlaerth JB, Mannel RS, Barakat R, 
Pearl ML, Sharma SK. Recurrence and survival after random assignment to laparoscopy versus 
laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group 
LAP2 Study. 
J Clin Oncol. 2012 Mar 1;30(7):695-700. doi: 10.1200/JCO.2011.38.8645. Epub 2012 Jan 30. 
Erratum in: J Clin Oncol. 2012 May 1;30(13):1570. 
 
4. Graves N1, Janda M, Merollini K, Gebski V, Obermair A; LACE trial committee. The cost-
effectiveness of total laparoscopic hysterectomy compared to total abdominal hysterectomy for the 
treatment of early stage endometrial cancer. BMJ Open. 2013 Apr 18;3(4). pii: e001884. doi: 
10.1136/bmjopen-2012-001884. Print 2013. 
 
5. Querleu D, Morrow CP. Classification of radical hysterectomy. 
Lancet Oncol. 2008 Mar;9(3):297-303. doi: 10.1016/S1470-2045(08)70074-3.  
 
6. Cibula D, Abu-Rustum NR, Benedetti-Panici P, Köhler C, Raspagliesi F, Querleu D, Morrow 
CP.New classification system of radical hysterectomy: emphasis on a three-dimensional anatomic 
template for parametrial resection. Gynecol Oncol. 2011 Aug;122(2):264-8. doi: 
10.1016/j.ygyno.2011.04.029. Epub 2011 May 17. 
 

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7..Abu-Rustum N, Khoury-Collado F, Pandit-Taskar N, Soslow R, Dao F, Sonoda Y, Levine D, 
Brown C, Chi D, Barakat R, Gemignani M. Sentinel lymph node mapping for grade 1 endometrial 
cancer: Is it the answer to the surgical staging dilemma? Gynecol Oncol 113(2009)163-169. 
 
8. Rossi EC, Ivanova A, Boggess JF. Robotically assisted fluorescence-guided lymph node 
mapping with ICG for gynecologic malignancies: A feasibility study. Gynecol Oncol. 2011. Oct 
11. 
 
9. Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics. 1982 
38: 143-151.  
 
19. Jung SH, Lee TY, Kim KM, George S. Admissible two-stage designs for phase II cancer 
clinical trials, Statistics in Medicine 2004 23: 561-569. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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21. Appendices 
 
Appendix 1. Anatomic description of lymphatic pathways draining the uterus 
 
 
 
The upper paracervical pathway (UPP) follows the uterine artery to the pelvic side wall draining 
primarily to the external iliac and obturator nodal compartments, then running lateral to the 
common iliac artery further to the paraaortic area. 
 

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The lower paracervical pathway (LPP) follows the ventral rim of the sacrouterine ligament, 
primarily to internal iliac and presacral nodes, then running medial of the common iliac artery 
further to the paraaortic area. 
 
The infundibulopelvic ligament pathway (IPP) runs via the Ip-ligament further to the 
supramesenteric paraaortic area. 
 
Assuming that lymph runs from the uterus and then cranially, supramesenteric paraaortic true 
SLN’s logically can only be defined when inframesenteric lymph are not ICG positive: 
Theoretically this may occur in situation when no pelvic nodes are dyed or when ICG have dyed 
pelvic nodes but not have been distributed further to the inframesenteric node, i.e that ICG goes 
directly to the supramestenteric nodes via the IP-ligament. 
Alternatively, when inframesenteric paraaortic nodes are ICG positive via the UPP and /or the LPP 
but no pelvic nodes in these pathways are dyed.  
 
For the pelvic SLN concept, ideally one SLN should be identified per LPP and UPP per pelvic side 
wall. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 2. Anatomical plan for localization of sentinel lymph nodes/ list of 
nodal specimens. 
 
Injection site of ICG  cervix                                     Reinjection cervix:  yes  no 
 
Display after first injection                                             Display after second injection 
 
 
                                                                                        
 
UPP 
LPP 
IP-
ligament 
Right 
 
 
 
Left 
 
 
 
 
 
 
 
 
 
Mark position and type of SLN on anatomical chart with number corresponding to position and 
number at list and on separate jars for each SLN.  
○ = ICG positive juxtauterine Sentinel node (SLN1) 
 
UPP 
LPP 
IP-
ligament 
Right 
 
 
 
Left 
 
 
 

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      = ICG neg juxtauterine lymph node with afferent lympahtic vessel (SLN 2) 
 
X =  Tumor suspect lymph nodes regardless of mapping (SLN makro) but with information on ICG 
positivity or not. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
List of nodal specimens (swedish)   Endometrial cancer             pat-id date 
 
 

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m preparat saknas från station stryks raden i listan.  Burknumrering behålls för övriga prep. 
 
KK 
Burk 
nr 
Körtelposition 
Patol 
burk
nr 
Dosa nr 
Antal bitar 
Mikro 
Antal 
körtlar 
Varav 
med 
metast 
1 Uterus, höger ovarium & tuba, 
vänster ovarium & tuba 
 
 
 
 
 
2 Lgl Iliaca Externa höger ICG NEG 
 
 
 
 
 
3 Lgl Iliaca Externa höger ICG POS 
 
 
 
 
 
4 Lgl Obturatorius höger ICG NEG 
 
 
 
 
 
5 Lgl Obturatorius höger ICG POS 
 
 
 
 
 
6 Lgl Iliaca Communis höger ICG 
NEG 
 
 
 
 
 
7 Lgl Iliaca Communis höger ICG 
POS 
 
 
 
 
 
8 Lgl Presacralt höger ICG NEG 
 
 
 
 
 
9 Lgl Presacralt höger ICG POS 
 
 
 
 
 
10 Lgl Iliaca Externa vänster ICG NEG 
 
 
 
 
 
11 Lgl Iliaca Externa vänster ICG POS 
 
 
 
 
 
12 Lgl Obturatorius vänster ICG NEG 
 
 
 
 
 
13 Lgl Obturatorius vänster ICG POS 
 
 
 
 
 
14 Lgl Iliaca Communis vänster ICG 
NEG 
 
 
 
 
 
15 Lgl Iliaca Communis vänster ICG 
POS 
 
 
 
 
 
16 Lgl Presacralt vänster ICG NEG 
 
 
 
 
 
17  Lgl Presacralt vänster ICG POS 
 
 
 
 
 
18 Lgl Paraaortalt nedom IMA ICG 
NEG 
 
 
 
 
 
19 Lgl Paraaortal nedom IMA ICG 
POS 
 
 
 
 
 
20 Lgl Paraaortal ovan IMA ICG NEG 
 
 
 
 
 
21 Lgl Paraaortalt ovan IMA ICG POS 
 
 
 
 
 
22 SLN Parametrium höger 
 
 
 
 
 
23 SLN Parametrium vänster 
 
 
 
 
 
24 SLN typ 1 presacralt höger 
 
 
 
 
 
25 SLN typ 1 presacralt vänster 
 
 
 
 
 
26 SLN typ 1 iliaca externa höger 
 
 
 
 
 
27 SLN typ 1 obturatorius höger 
 
 
 
 
 

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Numbers 30-34 will be used for describing locations outside the most common sites and for SLN 
type 2 and SLN macro as appropriate. The locations will be written by hand on list and labels for 
jars. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
28 SLN typ 1 iliaca externa vänster 
 
 
 
 
 
29  SLN typ 1 iliaca obturatorius 
vänster 
 
 
 
 
 
30 SLN typ 1 
 
 
 
 
 
31 SLN typ 1 
 
 
 
 
 
32 SLN typ 2 
 
 
 
 
 
33 SLN makro 
 
 
 
 
 
34 SLN makro 
 
 
 
 
 
35  
 
 
 
 
 

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Appendix 3.  Adverse events details/ descriptions logs. 
 
Intraoperative adverse events will be graded according to the following scale  
 
 
Grade 
Description 
Grade 1 
Mild; asymptomatic; not interfering with function. 
Grade 2 
Moderate; symptomatic; interfering with function but not 
ADL; medical intervention indicated. 
Grade 3 
Severe; symptomatic; interfering with ADL; 
operative intervention indicated; IV intervention 
indicated  
Grade 4 
Life-threatening; major urgent intervention indicated; 
disabling. 
Grade 5 
Death 
 
 
 
 

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Postoperative adverse events will be graded according to the Clavien Dindo classification 
 
Grade I Any deviation from the normal postoperative course without the need for pharmacological 
treatment or surgical, endoscopic and radiological interventions 
Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgetics, diuretics 
and electrolytes and physiotherapy. This grade also includes wound infections opened at 
the bedside. 
Grade 
II 
Requiring pharmacological treatment with drugs other than such allowed for grade I 
complications. 
Blood transfusionsand total parenteral nutritionare also included. 
Grade 
III 
Requiring surgical, endoscopic or radiological intervention 
       - 
IIIa 
Intervention not under general anesthesia 
       - 
IIIb 
Intervention under general anesthesia 
Grade 
IV 
Life-threatening complication (including CNS complications)* requiring IC/ICU-
management 
       - 
IVa 
single organ dysfunction (including dialysis) 
       - 
IVb 
multiorgandysfunction 
Grade 
V 
Death of a patient 
 
 
A. Adverse Events before docking the robot (during injection of ICG, insufflation, port 
placement and adhesiolysis) including conversions to open surgery.  
 
 
 
 
STUDY NUMBER 
AE/SAE 
DESCRIPTION 
Grade 
Attribution  
Example LU:019 
AE 
Converted, disseminated disea 1 
No 
Example KS :020 
AE 
Converted massive adhesions 
1 

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B. Adverse Events during sentinel node dissection
STUDY NUMBER 
AE/SAE 
DESCRIPTION 
Grade 
Attribution 
LU019   examples 
AE 
Bleeding requiring suture 
2 
KS020 
AE 
Obturator nerve damage 
3 

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C. Adverse events during completory pelvic/ pelvic + paraaortic  lymphadenectomy 
 
 
 
 
 
 
 
 
STUDY NUMBER 
AE/SAE 
DESCRIPTION 
Grade 
Attribution 
LU019 examples 
AE 
Bleeding requiring suture or 
2 
KS020 
AE 
Obturator nerve damage 
3 

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D. Adverse events during hysterectomy / omentectomy.  
  
 
 
 
 
 
 
 
 
STUDY NUMBER 
AE/SAE 
DESCRIPTION 
Grade 
Attribution 
LU019   examples 
AE 
Ureteral damage 
3 
KS020 
AE 
Bowel damage 
3 

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E. Postoperative adverse events until 30 postoperative days (all events, also potentially 
unrelated) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY NUMBER 
AE/SAE 
DESCRIPTION 
Grade 
Attribution 
LU019   examples 
AE 
Port hernia 
3 
KS020 
AE 
Fever of unknown origin 
2 

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Appendix 4. Serious adverse events log.  (one per patient ) 
 
 
Mail to Michele.bollino@med.lu.se 
 
Per definitions of SAE and attributions as outlined in protocol 
Attribution: Attribution is the determination of whether an adverse event is related to a 
medical treatment or procedure. The categories of attribution are: 
 
Definite: The adverse event is clearly related to the study drug/intervention  
Probable: The adverse event is likely related to the study drug/intervention. 
Possible: The adverse event may be related to the study drug/ intervention 
Unlikely: The adverse event is doubtfully related to the study drug/ intervention 
Unrelated: The adverse event is clearly NOT related to the study drug/intervention 
 
 
Patients study number  
Date for SAE  
Type of SAE 
Yes /no 
Attribution 
Death  
 
 
Life Threatening 
 
 
Drug /ICG related 
 
 
Intraoperative related the 
SLN procedure as such 
 
 
Intraoperative related the 
full LND/ hysterectomy 
 
 
Postoperative 
 
 
Unexpected AE 
 
 
 
Description / outcome of the SAE  
 
 
 
 

SLN-HREC Version 1.3 
SLN-HREC Version 1.3  
44 
 
 
 
 
 
 
 
 
Serious adverse event (SAE):  
An adverse event that results in one or more of the following: 
-Any death occurring prior to the postoperative outpatient evaluation 30 days postoperatively. 
-Any life-threatening event until and including 30 postoperative days. 
-Any medical event requiring inpatient hospitalization or prolongation of existing 
hospitalization beyond five postoperative days  
 
NOTE: Hospitalizations that are not considered SAE are: 
-Hospitalization planned prior to first administration of study drug 
-Hospitalization for elective treatment of a pre-existing condition unrelated to the study 
medication  
- Hospitalization due to social / practical reasons such as an untimely coordination with local 
community home care services.  
 
Attribution: Attribution is the determination of whether an adverse event is related to a 
medical treatment or procedure. The categories of attribution are: 
 
Definite: The adverse event is clearly related to the study drug  
Probable: The adverse event is likely related to the study drug. 
Possible: The adverse event may be related to the study drug. 
Unlikely: The adverse event is doubtfully related to the study drug. 
Unrelated: The adverse event is clearly NOT related to the study drug. 
 
Unexpected Adverse Event: An unexpected adverse event is an event not mentioned in the 
package insert/ manufacturer’s instructions or the specificity or severity of which is not 
consistent with the package insert/ manufacturer’s instructions. 

SLN-HREC Version 1.3 
SLN-HREC Version 1.3  
45 
The grading described beneath  and the attribution described above will be used for 
cathegorization of unexpected adverse events.