Short summary

The overall objective of this PhD is to initiate a national protocolled study on the implementation of sentinel lymph node (SN) mapping in women with early-stage cervical and endometrial cancer.

Study I is a randomized controlled study with comparison of self-rated incidence and severity of lymphedema in removal of SN alone versus removal of SN followed by complete removal of the pelvic lymph nodes in women with cervical cancer tumor smaller than 2 cm and low-/intermediate-risk endometrial cancer.

Study II is a prospective observational study where women with cervical cancer tumor size 2-4 cm and high-risk endometrial cancer will have SN removed followed by systematic removal of FDG-PET/CT positive lymph nodes and removal of all the pelvic lymph nodes to examine the negative predictive value.

We expect that the results from this project will have substantial significance in changing the national treatment strategy of both cervical and endometrial cancer patients in Denmark. 

Rationale

Removal of the pelvic lymph nodes is currently performed as a part of the surgical treatment of early stage cervical and endometrial cancer. Removal of the pelvic lymph nodes is considered as a staging procedure to allocate the woman to follow-up or further treatment while no survival benefit of routine pelvic lymphadenectomy has been found. Removal of the pelvic lymph nodes may result in chronic postoperative complications, e.g. numbness of the thighs and lasting retention of lymphatic fluid in the legs (lymphedema), which may affect the patient's quality of life. Studies have proved it safe for certain early stage cancers to use the so-called sentinel lymph node (SN) technique. The SN mapping concept is based on two principles; lymphatic drainage follows an orderly and predictable pattern to a regional lymph node basin and the first lymph node in this pattern functions as an effective filter for tumor cells. Hence, the SN is the first lymph node to which the primary tumor metastasizes. If the SN is without metastatic disease, studies show that all lymph nodes in that region are free of cancer and complete lymph node removal is unnecessary. By using this method removal of the pelvic lymph nodes can be avoided in many cancers without compromising the diagnostic safety. SN mapping is already implemented in the treatment of women with breast cancer and we wish to implement this highly specialized treatment in women with cervical- and endometrial cancer. SN mapping has proved safe in early stages of low-risk endometrial cancer and cervical cancer with a tumor size smaller than 2 cm. However, the effect on chronic complications and quality of life has yet to be evaluated. Our goal is to initiate a national protocolled study on the safe implementation of SN mapping which at the same time evaluates the effect of changing the operative treatment by patient reported outcome measures of lymphedema and quality of life. The SN mapping technique has not yet been proven safe in patients with high-risk endometrial cancer and cervical cancer with a tumor size 2-4 cm. We wish to evaluate the safety of implementing the SN technique for these patient groups in combination with systematic removal of FDG-PET/CT positive lymph nodes.

This PhD is work package two of the ROSOR project (Research On Surgical Robotics), a large multicenter project examining different aspects of robotic surgery. The current project examines techniques in robotic surgery, while the other work packages will be examining robotic surgery from an economical point of view, general quality of life after robotic surgery, muscular skeletal influences on the surgeon and development of the robotic function.

The results will qualify the available knowledge on the safety of the use of this new procedure to remove lymph nodes in early stage cervical and endometrial cancer. This project may have substantial significance in changing the national treatment strategy of both cervical and endometrial cancer patients.

Description of the cohort

Women with early stage cervical and endometrial cancer who according to the Danish Gynecologic Cancer Group's (DGCG) guidelines are referred to conventional radical removal of the pelvic lymph node at the Departments of Gynecology and Obstetrics at Odense University Hospital, Rigshospitalet and Herlev Hospital between March 2017 and March 2020 are eligible. Aarhus University Hospital is in the process of being included in the study. Patients will be recruited during their ambulatory visit prior to the surgery.

The project is divided into two overall studies, each with two sub-studies. The study populations are as follows:

• Study IA: Uterine cervical carcinoma, FIGO stage IB1, cervical tumor smaller than 2 cm
• Study IB: Endometrial adenocarcinoma, presumed FIGO stage I, Low risk: Type 1 grade 1 + 2
• Study IIA: Uterine cervical carcinoma, FIGO stage IB1, cervical tumor between 2 and 4 cm
• Study IIB: Endometrial adenocarcinoma, presumed FIGO stage I, High risk: Type 1 grade 3 + Type 2

Data and biological material

The randomized controlled trial (Study IA and IB):
Clinical data collected includes location and pathology of SNs and other excised lymph nodes. Incidence and severity of lymphedema will be evaluated using validated questionnaires:

• The generic questionnaire, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the disease specific instruments for cervical (CX-24) and endometrial (EN-24) will be used.
• Lymphedema Quality of Life Questionnaire (LYMQOL)

The questionnaires will be given to the patients pre-operatively, upon discharge and mailed to patients alive at 3, 12, 24, and 36 months after discharge.

The prospective study (Study IIA and IIB):
Clinical data includes FDG-PET/CT imaging results, location and pathology of SNs and other excised lymph nodes. 

Collaborating researchers and departments

Research Unit of Gynecology and Obstetrics, Odense University Hospital

• PhD student Sara Elisabeth Sponholtz, MD
• Chief Physician and Associate Professor Pernille Tine Jensen, PhD

Department of Gynecology and Obstetrics, Karolinska University Hospital, Sweden

• Chief Consultant and Professor Ole Mogensen, Professor, DMSc

Department of Nuclear Medicine, Odense University Hospital

• Chief Physician and Associate Professor Malene Hildebrandt, PhD

Department of Pathology, Odense University Hospital

• Chief Physician Doris Schledermann

The Maersk McKinney Moeller Institute, University of Southern Denmark

• Associate Professor Thiusius Rajeeth Savarimuthu, PhD

Rigshospitalet and Herlev Hospital are collaborating in the project and will aid in inclusion of patients. Preliminary accept of collaboration has also been obtained for Aarhus University Hospital.