Sentinel Node Detection in Cervical Cancer
Phase: NA
Conditions: Sentinel Lymph Node Biopsy
Sponsor: Region Skane

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Title page 
 
 
 
Sentinel node detection in cervical cancer. 
 
Date 180914 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 1. Participating Sites and Site-Principal Investigators 
 
Site 
         Site-PI 
                  # patients enrolled 
1.Department of Obstetrics and         Jan Persson MD, PhD                     XX 
Gynecology, Skåne University 
Hospital and Lund University, 
Lund, Sweden 
2. Department of Obstetrics and        Henrik Falconer  MD, PhD             YY 
Gynecology, Karolinska  
University Hospital and 
Karolinska Institute  
Stockholm Sweden 

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Coordinating Center: Department of Obstetrics and Gynecology, Skåne, Lund University 
Hospital and Lund University, Lund Sweden. 
   
 
Lead 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 
 
Local Principal Investigator: Henrik Falconer MD 
Department of Obstetrics and Gynecology Karolinska University Hospital 
Division of Gynecologic Oncology 
Adress Karolinska University Hospital 
Solna, 171 76 Stockholm, Sweden 
(ph) +468-517 700 00 
Email: henrik.falconer@karolinska.se 
 
Study Coordinator: Linnea Ekdahl MD 
Department of obstetrics and Gynecology, Division of Gynecologic Oncology 
Skåne University Hospital Lund 
SE-22185 Lund, Sweden 
(ph)+4646172093 
(fax) +4646156868 
Email: Linnea.ekdahl@med.lu.se 
 
Study Statistician: 
Filip Mörk. Faculty of Engineering, Lund University. 
 
 

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Overview study plan. 
 
 
Consecutive cervical cancer patients planned for robotic surgery, clinically stage 1A2 to 
2A1.  
 
 
 
 
 Cervical injection of ICG and a total of 80 MBq Tc99 nanocolloid (the first 75 patients) 
and if the combination of nanocolloid and ICG after analysisis better than ICG alone a 
continued combined use. If ICG or radiocolloid alone is equal or superior to the combined 
use in terms of technical success rates, the study will continue with the use of ICG or 
radiocolloid alone as tracer according to sample size analysis. 
 
 
 
 
 
Registration of adverse events during insufflation and placement of port including 
necessary adhesiolysis.  
 
 
 
 
Pelvic SLN identification with near infrared technique (and gamma probe first 75 patients) 
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. 
 
 
 

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Frozen section of SLN and upper lymphovascular parametria. 
 
 
 
 
 
 
A full pelvic lymphadenectomy after removal of SLN according to the Swedish National 
treatment protocol extended to the level of the inferior mesenteric artery in case of 
metastatic SLN’s.  Robotic Surgery with a Querleu Morrow B2 to C2 radical hysterectomy 
as appropriate or an aborted hysterectomy in case of metastatic SLN. Adnexal surgery as 
appropriate. 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. Analysis of technical success rates, sensitivity and false 
negative rates for SLN’s comparing ICG with Radiocolloid after first 75 patients. In case of 
ICG + radiocolloid superior to ICG alone continued enrollment of patients using both tracers. 
In case of any of ICG or radiocolloid alone equal or superior to the combination continuation 
of the study for an interim analysis after 36 node positive patients (see section 11). 
 
 
 

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Table of contents  
 
1.0 
OBJECTIVES 
 
 
2.0 
BACKGROUND  
 
 
3.0 
PATIENT AND SURGEON ELIGIBILITY 
 
 
4.0 
STUDY MODALITIES 
 
 
5.0 
TREATMENT PLAN 
 
 
6.0 
TREATMENT MODIFICATIONS 
 
 
7.0 
STUDY CRITERIA 
 
 
8.0 
EVALUATION CRITERIA 
 
 
9.0 
DURATION OF STUDY 
 
 
10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
 
12.0 
BIBLIOGRAPHY 
 
 

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1. OBJECTIVES 
 
To estimate ICG and Radiocolloid alone and in combination to estimate any advantage of 
the combination of both tracers in terms of technical success rates/ bilateral mapping, 
sensitivity and false negative rates for the detection of pelvic SLN (first 75 patients).  
 
To estimate the sensitivity and negative predictive value of the pelvic sentinel lymph node  
(SLN)  concept for determination of lymph node metastases in patients with early stage 
cervical cancer planned for robotic surgery using either a combination of ICG and 
Radiocolloid or in case ICG alone is equal to or superior (in terms of technical success rate, 
bilateral mapping rates) to the combination the use of ICG as tracer for cervical injection 
using an anatomically based surgical algorithm and definition of sentinel lymph nodes.  
 
To estimate if reinjection of tracer (ICG) will enhance the technical success / bilateral 
mapping rates. 
 
To estimate the proportion of cervical cancer patients suitable for the SLN concept in 
conjunction with robotic surgery 
 
To estimate complications associated with the detection and removal of SLN as such. 
 
To estimate complications associated with ICG as tracer. 
 
To estimate the incidence of lymphatic complications by the use of a validated 
questionnaire 
 
 
 
 
 
 
 
 

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2. BACKGROUND  
 
The surgical approach for cervical cancer staging has changed from conventional 
laparotomy to a more minimally invasive technique with proven advantages in terms of less 
perioperative morbidity. Robotic assisted laparoscopic radical hysterectomy with pelvic 
lymph node dissection has emerged as the approach of choice for an increasing number 
gyne-oncologists worldwide. Previous data from the department of Obstetrics and 
Gynecology in Lund, Sweden, shows that robot assisted surgery feasible for 95% of 
unselected cervical cancer patients selected for primary surgery.  
In cervical cancer, nodal involvement is a strong prognostic factor and also determines 
adjuvant treatment and a pelvic lymphadenecomy is recommended for cervical cancer 
stages 1a2 and higher stages where primary surgery is recommended. A pelvic 
lymphadenectomy is associated with an increased risk for lymphatic complications such as 
lymphedema, lymphocysts and in rare cases lymphatic ascites.  
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 the 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.  Moreover, technical success rate varies. A high 
technical success rate is cruzial to avoid the need for a full hemipelvic or pathwaywize 
LND in case of failure. In pilot studies from Lund University we have shown that 
reinjection of tracer ( ICG)  increases the technical success rates both defined per 
hemipelvis and pathwaywize, defined by detection of at least one SLN per hemipelvis to 
around 95%. By the use of Indocyanine green, a fluorescent tracer, we have also previously 
demonstrated two bilateral separate pelvic pathways, the upper paracervical pathway (UPP) 
running along the upper lymphovascular  parametrium usually to  external iliac and/ or 
obturator nodes and the further lateral to the common iliac artery to paraaortic nodes and 
the lower paracervical pathway (LPP) running via the sacrouterine 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.  
 

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Surgical competence and experience is necessary to achieve a high technical success rate 
and a low false negative rate for SLN.  
This study aims to evaluate the pelvic sentinel node concept based on a defined surgical 
algorithm and with a clear definition of SLN based on described uterine lymphatic 
anatomy. The study setting including only high volume surgeons at two of more tertiary 
high volume centers enables an evaluation of the true potential of the pelvic SLN concept in 
cervical cancer.   
 
This study aims to include consecutive early stage (Stage 1a2 to 2a1) cancer patients 
fulfilling criteria to ensure the results is representative for the cervical cancer population. 
Planned surgery may be a radical hysterectomy or a radical trachelectomy including a full 
LND after removal of identified SLN’s or an aborted procedure in favour of 
radiochemotherapy in case of metastatic SLN’s. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3. PATIENT ELIGIBILITY 
 
Inclusion Criteria 
-Women of age 18 years and older at the time of informed consent. 
-Women with a pathologically proven cervical carcinoma of any histologic subtype, 
clinically stage 1a2- 2a1 planned for primary surgery 
-Absence of any exclusion criteria 
 
 
 
Exclusion Criteria 
-Non consenting patients 
-Ongoing pregnancy 
-Inability to understand written and/or oral study information  
-Who performance status III or more 
-Previous lower limb lymphedema 
-Surgical contraindication to a laparoscopic approach or lymphadenectomy at surgeons 
discretion. 
-Anesthesiologic contraindication to a laparoscopic approach at the anesthetist’s discretion  
- Locally advanced disease or intraabdominal/distant metastases at preoperative CT, MRI or 
ultrasonography  
- Radiologically suspect pelvic nodal metastatic disease according to the RECIST criteria 
(>= 1 node with >=16 mm short axis diameter) 
-Allergy to Iodine  
-Patients with a known liver disease 
-Patients with a significant bleeding disorder or mandatory antithrombotic treatment.  
 
 
 
 
 
 

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Before surgery patients will be allocated to:   
 
Primarily: Removal of pelvic SLN’s followed by a complete pelvic lympadenectomy with 
boundaries as described below. SLN and the separately removed upper paracervical tissue 
will be sent for frozen section and later for ultrasectioning and immunohistochemistry. 
A Querleu Morrow B2 to C2 radical hysterectomy or a robotic abdominal radical 
trachelectomy will be performed and at surgeons’ discretion an abortion of those 
procedures in case of metastatic SLN’s. Adnexal surgery / transpositioning of the adnexae 
will be performed at surgeons’ discretion and patients wish. 
 
 
Surgeon eligibility     
All included surgeons outside the primary investigating center must have had a case 
observation at the primary investigating center  followed by a 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. 
 
The departments of pathology were coordinated in terms of principles for ultrasectioning 
and immunohistochemistry of SLN and management on non-sentinel lymph nodes. 
 
 
  
 
 
 
 
 
 
 
 

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4.0  STUDY MODALITIES 
 
Surgical Procedures 
 
- Patients with stage 1a2- 2a1 cervical cancer planned for primary surgery with either a 
Querleu-Morrow B2- C2 radical hysterectomy or a robotic radical trachelectomy. 
- Injection of tracer (a total of 80 MBq Technetium nanocolloid  and 2,5mg ICG solution / 
2,5 mg/mL) will be injected submucosally into the cervix ad 2-4-8-and 10 O’clock 
respectively at onset of surgery (first 75 patients). 
- Scanning of pelvic side walls after a minimum of 20 minutes after injection and a 
transperitoneal or retroperitoneal evaluation of ICG uptake per pathway ( UPP and LPP 
bilaterally)  
- Detection and removal of SLN will follow a strict protocol with a proximal- presacral 
dissection before the distal external iliac-obturator nodal compartment dissection and with 
careful opening of the presacral, paravesical and pararectal planes to avoid leaking of tracer. 
SLN will be defined as describe below. 
- Identified SLN’s and the upper paracervical tissue will be sent for frozen section and 
further for final ultrasectioning and immunohistochemistry as described below. 
- A full pelvic nodal dissection will be performed after the removal of SLN’s. 
- The described procedures in this protocol will be performed with robot-assisted 
laparoscopy and with removal of SLN and non-SLN’s before the radical hysterectomy/ 
trachelectomy. 
 
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 

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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. 
 
 
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 
 
 
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 submucosally 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 

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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). 
 
Technetium 99 Nanocolloid 
The nanocolloid (GitPharma S.R.L. Saluggia Italy) will be prepared at the radionuclide unit  
at Skåne University Hospital, Lund, 1-2 hours before injection in four separate syringes 
each contacting 0,5mL and 20 MBq nanocolloid. The injection was performed the same 
was as described above and performed before the injection of ICG. A laparoscopic gamma-
probe (Neo2000© laparoscopic probe, Neoprobe Corporation Dublin OHIO) will be used 
for detection of the SLN’s defined by radiotracer. 
 
Sentinel Node Identification 
The bilateral technical success rate of SLN identification is important to determine if this 
technique can be transferred to clinical practice. Previous studies at our institution using 
Technetium 99 Nanocolloid as single tracer have shown a bilateral mapping rate of 65% in 
tumors smaller than 20 mm and in all size cervical cancer of 59%. Based on pilot studies at 
our institution on cervical and endometrial cancer with the use of ICG we expect that the 
bilateral pelvic SLN identification (defined as at least one SLN per hemipelvis) 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.  
A clear anatomically definition of what is a SLN and a strict surgical algorithm as described 
in this study is important. 
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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The sentinel nodes are defined as the juxtauterine ICG positive / radiopositive 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 ICG type 2.  
The definitions based on ICG positive lymphatic channels were only attributed for nodes 
defined by ICG but does not exclude that nodes were also defined by radiopositivity. 
Nodes macroscopically suspect of metastatic disease will be defined as SLN Macro 
regardless of ICG uptake or radiopositivity but with information on ICG and 
radiopositivity. 
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 names and numbers. The SLN will be defined as SLNICG,  
SLNICG+Radio, and SLNRadio and for SLN defined by ICG also as type 1 and 2.  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, the types of SLN as of above 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. 
SLN’s will be sent for frozen section and final histological evaluation including 
ultrasectioning and immunohistochemistry as described. SLN’s will be sent for frozen 
section during surgery for intraoperative decisions on the extent of lymphadenectomy 
 (paraaortic or not), transposition of ovaries and abortion of the hysterectomy in favour of 
radiochemotherapy.. 
 
Before final removal of SLN, the pelvic side walls will be scanned with the gamma-probe 
to get an overview of radiopositivity per hemipelvis including the presacral area. After 
opening of the avascular planes as of below a renewed scanning with the probe will be 
performed. Finally, in case no SLN radio have been identified per pathway, a final scan 
with the probe will be performed after removal of SLN’s.  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 

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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 a non-display of a pathway an ipsilateral injection of ICG as described 
will be performed. (the comparison of bilateral mapping rates between ICG and radiotracer 
will be performed before any second injection of ICG).Another 10 minutes will be alloved 
for awaiting distribution of ICG in the respective pathways. To minimize disturbance by 
leaking ICG or radiotracer  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 compartmentwize  pelvic lymphadenectomy is 
performed followed by the hysterectomy as appropriate.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Anatomical boundaries of lymph node compartments in the female pelvis 
 
Lymph node 
compartment 
Proximal limit 
Lateral limit 
Distal limit 
Medial limit 
External iliac 
area 
Bifurcation of 
external and 
internal iliac 
artery 
Genitofemoral 
nerve 
Cloquets lymph 
node 
External iliac 
vein 
Obturator fossa 
Internal iliac 
vein 
Ileopsoac muscle 
Os pubis, 
obturator nerve 
Obliterated 
umbilical artery 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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. 
 
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. 
 

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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  paraaortic 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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Anatomic plan for localization of sentinel lymph nodes 
 
Injection site of ICG and Tc99nanocolloid   cervix                   Reinjection ICG  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) 
 
      = ICG neg juxtauterine lymph node with afferent lympahtic vessel (SLN 2) 
 
X =  Tumor suspect lymph nodes regardless of mapping (SLN makro) 
 
UPP 
LPP 
IP-
ligament 
Right 
 
 
 
Left 
 
 
 

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List of nodal specimens ( swedish)  Cervical cancer ICG+TC99  ID  date  
Om preparat saknas från station stryks raden i listan.  Burknumrering behålls för övriga prep. 
 
KK 
Burk 
nr 
Körtelposition 
Patol 
burknr 
Dosa 
nr 
Antal bitar 
Mikro
Antal 
körtlar 
Varav 
med 
metast 
1 Uterus, höger ovarium & tuba, 
vänster ovarium & tuba 
 
 
 
 
 
2 Höger tuba 
 
 
 
 
 
3 Vänster tuba 
 
 
 
 
 
4 SLN Parametrium höger 
 
 
 
 
 
5 SLN Parametrium vänster 
 
 
 
 
 
6 Lgl Externa höger ICG NEG Techn NEG 
 
 
 
 
 
7 Lgl Externa höger ICG  POS Techn NEG 
 
 
 
 
 
8 Lgl Externa höger ICG POS Techn POS 
 
 
 
 
 
9 Lgl Externa höger ICG NEG Techn POS 
 
 
 
 
 
10 Lgl Obt. höger  ICG NEG Techn NEG 
 
 
 
 
 
11 Lgl Obt. höger ICG POS Techn NEG 
 
 
 
 
 
12 Lgl Obt. Höger ICG POS Techn POS 
 
 
 
 
 
13 Lgl Obt. Höger ICG NEG Techn POS 
 
 
 
 
 
14 Lgl Comm höger  ICG NEG Techn NEG 
 
 
 
 
 
15 Lgl Comm höger ICG POS  Techn NEG 
 
 
 
 
 
16 Lgl Comm höger ICG POS Techn POS 
 
 
 
 
 
17 Lgl Comm höger ICG NEG Techn POS 
 
 
 
 
 
18 Lgl Presacralt hö ICG NEG Techn NEG 
 
 
 
 
 
19 Lgl Presacralt hö ICG POS Techn NEG 
 
 
 
 
 
20 Lgl Presacralt hö ICG POS Techn POS 
 
 
 
 
 
21 Lgl Presacralt hö ICG NEG Techn POS 
 
 
 
 
 
22 Lgl Externa vä  ICG NEG Techn NEG 
 
 
 
 
 
23 Lgl Externa vä ICG POS Techn NEG 
 
 
 
 
 
24 Lgl Externa vä ICG POS Techn POS 
 
 
 
 
 
25 Lgl Externa vä ICG NEG Techn POS 
 
 
 
 
 
26 Lgl Obt. vänster ICG NEG Techn NEG 
 
 
 
 
 
27 Lgl Obt. vänster ICG POS Techn NEG 
 
 
 
 
 
28 Lgl Obt. vänster ICG POS Techn POS 
 
 
 
 
 
29 Lgl Obt. vänster ICG NEG Techn POS 
 
 
 
 
 
30 Lgl Comm vänster  ICG NEG Techn NEG 
 
 
 
 
 
31 Lgl Comm vänster ICG POS  Techn NEG 
 
 
 
 
 
32 Lgl Comm vänster ICG POS Techn POS 
 
 
 
 
 
33 Lgl Comm vänster ICG NEG Techn POS 
 
 
 
 
 
34 Lgl Presacralt vä ICG NEG Techn NEG 
 
 
 
 
 

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SLN anges i fritext i tabell och med tryck RÖD klisteretikett på burk.  Vid behov av sep histologi (tex bulky 
nodes) används fritext i tabell och numrering 50 ff samt etikett+ fritext  på burk avseende lokal / orsak 
 
Sentinel node definieras som den mest uterusnära ICG pos körteln i respektive kompartment där man 
identifierar en separat afferent lymfbana 
 
 
35 Lgl Presacralt vä ICG POS Techn NEG 
 
 
 
 
 
36 Lgl Presacralt vä ICG POS Techn POS 
 
 
 
 
 
37 Lgl Presacralt vä ICG NEG Techn POS 
 
 
 
 
 
38 Lgl Ned aortabif ICG NEG TECHN NEG 
 
 
 
 
 
39 Lgl Ned aortabif ICG POS TECHN NEG 
 
 
 
 
 
40 Lgl Ned aortabif ICG POS TECHN POS 
 
 
 
 
 
41 Lgl Ned aortabif ICG NEG TECHN POS 
 
 
 
 
 
42 Lgl Paraaortal nedom IMA 
ICG NEG Techn NEG 
 
 
 
 
 
43 Lgl Paraaortal nedom IMA 
ICG POS Techn NEG 
 
 
 
 
 
44 Lgl Paraaortal nedom IMA 
ICG POS Techn POS 
 
 
 
 
 
45 Lgl Paraaortal nedom IMA 
ICG NEG Techn POS 
 
 
 
 
 
46 SLN typ 1 ICG POS Techn Neg 
 
 
 
 
 
 
47 SLN  typ 1 ICG POS Techn Neg 
 
 
 
 
 
 
48 SLN  typ 1 ICG POS Techn Neg 
 
 
 
 
 
 
49 SLN typ 1 ICG POS Techn POS 
 
 
 
 
 
 
50 SLN typ 1 ICG POS Techn POS 
 
 
 
 
 
 
51 SLN typ 1 ICG POS Techn POS 
 
 
 
 
 
 
52 SLN typ 2 ICG NEG Techn NEG 
 
 
 
 
 
 
53 SLN typ 2 ICG NEG Techn NEG 
 
 
 
 
 
 
54 SLN typ 2 ICG NEG Techn POS 
 
 
 
 
 
 
55 
 
SLN Makro   ICG pos   radio pos 
                       ICG neg   radio neg 
 
 
 
 
 
56 
 
SLN Makro   ICG pos   radio pos 
                       ICG neg   radio neg 
 
 
 
 
 
57 
 
 
 
 
 
 
 

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List of nodal specimens (Swedish)  cervical cancer  Tracer ICG   pat-id date  
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 
 
 
 
 
 
28 SLN typ 1 iliaca externa vänster 
 
 
 
 
 
29  SLN typ 1 iliaca obturatorius 
vänster 
 
 
 
 
 
30 SLN typ 1 
 
 
 
 
 
31 SLN typ 1 
 
 
 
 
 

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Om preparat saknas från station stryks raden i listan.  Burknumrering behålls för övriga prep. 
 
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. 
 
 
Histopathologic evaluation of the sentinel nodes and the non-sentinel nodes. 
At final pathological examination, all macroscopically identified SLN lymphoid tissue will 
be embedded and bisected at the minimum thickness exceeded 3 mm. Ultrastaging using 
hematoxylin/ Eosin staining  will be performed in five sections at three different levels , 
separated by 200 µm. First and second level immunohistochemistry (pan-cytokeratin, MNF 
116) will be performed if the maximum diameter of the SLN tissue exceeds one mm. 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. 
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. 
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: 
Macrometastases = tumor greater than 2.0 mm in diameter. 
Micrometastases = 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. 
 
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. 
32 SLN typ 2 
 
 
 
 
 
33 SLN makro  ICG pos 
                     ICG neg 
 
 
 
 
 
34 SLN makro   ICG pos 
                       ICG neg 
 
 
 
 
 
35  
 
 
 
 
 

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5.0 TREATMENT PLAN 
-Intraoperative cervical injection of Tc 99 nanocolloid and ICG (immediately before onset 
of surgery)  
-Intraoperative lymphatic mapping and sentinel node identification with robotic 
NIR/fluorescence imager and gamma probe will be used for an initial transperitoneal, then 
retroperitoneal evaluation of display of ICG fluorescence/ radiopositivity. The 
retroperitoneal dissection with opening of the avascular planes saving the lymphatic vessels 
will start presacrally then further with the pelvic side walls. The upper lymphovascular 
parametria will be kept intact by a careful opening of the pararectal and paraveiscal 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 15-20 
minute search, the case should be described as a ICG-negative mapping event for that 
pathway. A initial scanning of the pelvic side walls and presacral area will be performed  
- A reinjection of ICG will be performed in case of non-display of any of the UPP and LPP 
bilaterally. 
-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, ICG defined) and / or radio negative mapping  any 
macroscopically metastase  suspect nodes should be removed and defined as SLN macro. 
All patients will be subject for at least a full pelvic lymphadenectomy after removal of 
SLN. 
-The upper lymphocascular parametrial tissue (the tissue medial of the obliterated umbilical 
artery, with the supravesical 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.  
- The SLN’s and separate upper parametria will be sent for frozen section. 
 
-All SLN and the upper parametrial tissue will be subject for later ultrasectioning and IHC 
Histopathologic evaluation.  
 
 
 

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- In case of metastatic SLN the lymphadenectomy will be extended to the level of the 
inferior mesenteric artery and the hysterectomy aborted in favour of 
radiochemoptherapy. In case of a planned trachelectomy this will be transformed to 
a radical hysterectomy. 
-A Querleu-Morrow type B2 or C2 hysterectomy or robotic radical trachelectomy will be 
performed as appropriate or aborted in case of metastatic LSN at surgeons discretion and 
patients’ wish. 
- Adnexal surgery or transpositioning of the adnexa shall be performed at surgeons 
discretion and patient’ wish. 
 
-  Complications will be recorded and subdivided to enable association with parts of the 
procedure, most importantly, the SLN procedure as such and the lymphadenectomy. The 
classification described under the adverse events tables will be used. 
 
NOTE: Surgeon skill and adherence to protocol will be verified as described. 
 
 
 

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6.0  TREATMENT MODIFICATIONS 
 
In case of no ICG uptake (including reinjection according to protocol) or radiopositivity the 
overall SLN algorithm should be followed, i.e removal of any macroscopically suspect 
nodes and as planned a full compartmentwize lymphadenectomy. 
 
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. 
 
In case of metastatic SLN on frozen section, the lymphadenectomy should be extended to 
the level of the inferior mesenteric artery, a planned trachelectomy converted to a radical 
hysterectomy and at surgeons discretion and patient wish a planned radical hysterectomy 
completed or aborted in favour of radiotherapy. Adnexal surgery / transposition of ovaries 
shall be performed at surgeons’ discretion and patient wish. 
 
 
 

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7.0  STUDY CRITERIA 
 
Observations and Tests 
 
The following observations and tests are to be performed and, where appropriate, recorded 
on the designated form(s) (Appendix A): 
 
PARAMETER 
Pre-operative 
Intraoperative 
Postoperative 
Log on approached patient   
X 
 
Log on included patients and 
patients’ withdrawal from study 
before surgery 
X 
History & Physical examination 
Examination and evaluation by 
surgeon and anesthetist 
X 
Laboratory test 
Hb, S-electrolytes, S-kreatinine 
CRP, Trc, coagulation test when 
appropriate  
X  
X 
Injection data for ICG including 
drug related adverse events  
X 
X 
X 
Sentinel nodes identification 
X 
Recording of intraoperative 
adverse events  
X   

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Adverse Events will be captured from time of ICG administration until30 days after surgery  
 
Histologic evaluation of sentinel 
nodes and non-sentinel nodes 
X 
Recording of  post-op 
complications until 30 days after 
surgery 
X 
Recording of lymphatic 
complications on validated 
questionnaire at symptoms and at 
one year after surgery 

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8.0  EVALUATION CRITERIA 
 
-Technical success rates, sensitivity and false negative rates with ICG and Tc99 
nanocolloid will be compared per patient, per hemipelvis and per pathway, UPP and LPP.  
 
- All patients who are injected with tracer 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 hemipelvis and per separate pathway) after first and in case of 
non-dispay of any of the LPP and UPP after reinjection of ICG as described.  
 
- Patients with at least one SLN type1-2 identified will be included for determining the 
sensitivity and the negative predictive value for the SLN ICG concept. In addition the 
overall SLN concept, including SLN macro  will be evaluated as of above.  
 
- All patients included, regardless of conversion to open surgery and mapping of ICG (or 
the combination of ICG and Tc99 nanocolloid) will be included in the evaluation of 
feasibility and safety. 
 
- Intraoperative adverse associated with the detection and removal of SLN will be evaluated 
and reported separately on all patients who have at least one SLN removed regardless of 
type, i.e all patients in whom SLN were removed separately. 
 
- Postoperative complications until 30 days after surgery will be reported.  
 
-The incidence of lymphatic complications defined by the questionnaire will be evaluated 
 
 
 
 
 
 
 

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9.0  DURATION OF STUDY 
 
The study includes a radical hysterectomy/ radical abdominal trachelectomy with detection 
of SLN followed by a full pelvic lymphadenectomy along both the UPP and LPP. 
  
The patient may withdraw from the protocol at any time prior to surgery or at any time until 
retrieval of postoperative data until one year  after surgery.  
 
The study is initiated at Lund University hospital with a planned later inclusion of the 
second investigating center which may motivate a revision of the study protocol related 
estimated time for enrollment of patients and for accreditation of the second centre  and 
surgeons. 
 
Assuming that the prevalence of pelvic lymph node metastases is 15 % 227 patients will be 
needed to obtain 34 lymph node positive observations. Given a 95% bilateral detection rate 
of SLN’s approximately 15 patients more will need to be included. On the other hand, 
ultrasectioning and IHC of SLN’s is estimated to increase the proportion of patients with 
nodal metastases by identifying micro metastases. As there will be a continuous report of 
node positive patients to the study coordinator an interim analysis will start after 36 node 
positive 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 28 node positive patients (total 187 patients)  will 
be required. (see 11, statistical considerations) 
Given an estimate that the accrual rate is 2,5 cervical cancer patients per month per center, 
a total of 45 months will be required to reach 226 cervical cancer patients and a total of an 
additional 37 months to reach 413 patients. 
 
 

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10 STUDY MONITORING AND REPORTING PROCEDURES 
 
ADVERSE EVENT REPORTING 
 
The study protocol has been revised related principles study monitoring and for reporting 
adverse events to the principal investigating center after inclusion of the second center.  
 
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. 
 
This study will utilize the Adverse Events Logs (Tables 10.1-5). Any SAE will be reported 
to the study coordinator linnea.ekdahl@med.lu.se  or jan.persson@med.lu.se  
 
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. 
 

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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. 
The grading described beneath and the attribution described above will be used for 
cathegorization of unexpected adverse events. 
 
 

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Participating Center Reporting Responsibilities 
 
Reporting to the study coordinator 
Any SAE’s must be reported to study Coordinator at Lund University Hospital within 3 
working days of discovery of the incident, using the study-specific SAE Form. 
Email: linnea.ekdahl@med.lu.se 
 
The lead and local principal investigators and the study coordinator shall conduct 
continuous review of data and patient safety for a monthly summary of the included 
number of patients, patient safety and significant AE’s described in the protocol.  
 
All SAE’s potentially associated with the study drug, the sentinel node procedure as such or 
deaths shall be evaluated by a  
 
 
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 

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sentinel node procedure as such, are life threatening or resulting in death (defined above 
and in table 10.6) to the respective Safety Monitoring Committees (SMC) for clinical 
studies at Skåne University Hospital or local investigating centre 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. 
 
 
10.1.4. 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. 
 
Data Management 
Preoperative, intraoperative and postoperative data from each surgery will be recorded on 
the standardized study sheets.These study sheets will be made 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 “1” and the first 

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study patient will have the study number “1-001. 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). 
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.
Kommenterad [PJJ1]: 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.   

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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. 
 
10.1.8. Protocol Deviations 
Major protocol deviations shall be reported by mail to the study coordinator. 
linnea.ekdahl@med.lu.se, or Jan.persson@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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 10.1. 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 LU001 
AE 
Converted, disseminated disea 1 
Example LU002 
AE 
Converted massive adhesions 
1 

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Table 10. 2. Adverse Events during sentinel node dissection
STUDY NUMBER 
AE/SAE 
DESCRIPTION 
Grade 
Attribution 
LU001  examples 
AE 
Bleeding requiring suture 
2 
LU002 
AE 
Obturator nerve damage 
3 

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Table 10.3. Adverse events during completory pelvic lymphadenectomy 
 
 
 
 
 
 
 
 
STUDY NUMBER 
AE/SAE 
DESCRIPTION 
Grade 
Attribution 
LU001examples 
AE 
Bleeding requiring suture or 
2 
LU002 
AE 
Obturator nerve damage 
3 

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Table 10.4. Adverse events during hysterectomy/ trachelecomy 
  
 
 
 
 
 
 
 
STUDY NUMBER 
AE/SAE 
DESCRIPTION 
Grade 
Attribution 
LU001 examples 
AE 
Ureteral damage 
3 
LU002 
AE 
Bowel damage 
3 

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Table 10.5. Postoperative adverse events until 30 postoperative days (all events) 
 
 
 
 
 
 
 
 
STUDY NUMBER 
AE/SAE 
DESCRIPTION 
Grade 
Attribution 
LU001  examples 
AE 
Port hernia 
3 
LU002 
AE 
Fever of unknown origin 
2 

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Table 10.6 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11. STATISTICAL CONSIDERATIONS 
This study is designed to evaluate the application of the sentinel node (SLN) technique in 
determining the pelvic lymph node (LN) status in patients with early stage cervical cancer ( 
stage 1a2 to 2a1) planned for primary surgery with either a radical hysterectomy or radical 
abdominal trachelectomy. 
The main statistical endpoint will be sensitivity and false negative rates /negative predictive 
value calculated per patient. The sensitivity is the proportion of patients who test as SLN (+) 
among the patients who have LN metastases (LN+). The patients will, according to the 
Swedish national guidelines for early stage cancer undergo a full 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 time for accrual may have to be revised revised after inclusion of additional 
participating centers. 
We used the Fleming two stage design for evaluation of study termination for evaluating if 
the technique is not working well, as expected or better (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 ≥ 95% or if 
sensitivity is significantly higher than 85%. In the first stage, 34 LN+ patients will be 
accrued. If there are 30 or fewer responses in these 34 patients, the study will be stopped for 
futility. If there are at least 33 responses in 33 patients, the study will be stopped and the 
null hypothesis rejected. Otherwise, 28 additional patients will be accrued for a total of 62 
node positive patients. The null hypothesis will be rejected if 58 or more responses are 
observed in 62 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 226 patients to be included taking into 
consideration a 95% bilateral SLN detection rate, and an estimated 15% rate of node 
positivity including an increase in node positivity rates due to ultrasectioning and 
immunohistochemistry. For the second stage, another 187 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.  
       

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BIBLIOGRAPHY 
 
1. Querleu D, Morrow CP. Classification of radical hysterectomy. 
Lancet Oncol. 2008 Mar;9(3):297-303. doi: 10.1016/S1470-2045(08)70074-3.  
 
2. 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. 
 
3.Darlin L1, Persson J, Bossmar T, Lindahl B, Kannisto P, Måsbäck A, Borgfeldt C. 
The sentinel node concept in early cervical cancer performs well in tumors smaller than 2 
cm. Gynecol Oncol. 2010 May;117(2):266-9. doi: 10.1016/j.ygyno.2010.01.035. Epub 2010 
Feb 18. 
 
 
4. Persson J, Kannisto P, Bossmar T. Robot-assisted abdominal laparoscopic radical 
trachelectomy. Gynecol Oncol. 2008 Dec;111(3):564-7. doi: 10.1016/j.ygyno.2008.05.034. 
Epub 2008 Jul 11. 
 
 
5. 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. 
 
6.  Geppert B, Lönnerfors C, Bollino M, Arechvo A, Persson J. 
A study on uterine lymphatic anatomy for standardization of pelvic sentinel lymph node 
detection in endometrial cancer. Gynecol Oncol. 2017 May;145(2):256-261. doi: 
10.1016/j.ygyno.2017.02.018. Epub 2017 Feb 10. 
 
7. Fleming TR (1982). One-sample multiple testing procedure for phase II clinical trials. 
Biometrics 38: 143-151.  

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8. Jung SH, Lee TY, Kim KM, George S (2004). Admissible two-stage designs for phase II 
cancer clinical trials, Statistics in Medicine 23: 561-569. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 1  SAE events log 
 
Serious adverse events log.  Mail to linnea.ekdahl@med.lu.se or 
jan.persson@med.lu.se 
 
 
 
Per definitions of SAE and attributions as outlined in protocol 
 
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  
 
 
 
 
 
 
 
 
 

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