Magtrace® as tracer for sentinel lymph node
detection in early stage epithelial ovarian
cancer: a pilot study

Epithelial ovarian cancer (EOC) remains the tumour with the most unfavourable
prognosis within the field of gynaecological oncology. The incidence of ovarian
cancer in the Netherlands in 2008 was 14.5 per 100.000, with 12.3 deaths per
100.000 [1]. In the US in 2007 the incidence was 13.0 per 100.000 and there
were 8.2 deaths per 100.000 [2]. The high mortality rate is partially due to
the fact that approximately 75% of patients is diagnosed with advanced stage
EOC [3]. The remaining 25% of patients are diagnosed in an early stage, which
require a complete surgical staging procedure including pelvic and para-aortic
lymphadenectomy. Although this lymphadenectomy is standard-of-care, it leads to
significant morbidity in these patients. Mainly direct postoperative
complications such as infection, repeat surgery and early death have been
reported [4]. Also, long-term complications such as lymph cysts or lymphedema
have been described.
A potential method to reduce this morbidity and mortality, as already been
described in other cancers such as breast cancer and vulvar cancer, is
utilizing a sentinel lymph node (SLN) technique. By identifying and resecting
the SLN, the patient is potentially spared form lymphadenectomy.

2.1 Background
EOC can metastasize through three different pathways: intraperitoneal (in the
abdominal cavity), lymphogenous or haematogenous [5,6]. Concerning the
lymphogenous spread, it is clear that lymphatic spread of EOC occurs mainly to
the para-aortic lymph nodes [7]. It is theorized that the tumour cells follow
the lymph vessels that accompany the ovarian vessels in the infundibulopelvic
ligament up to the upper para-aortic region and renal vein. Additionally,
pelvic lymph node metastases are also frequently found [8]. These tumour cells
probably follow a different route, migrating via the para-uterine vessels in
the broad ligament towards the uterine vessels and further on to the iliac
vessels and lymph nodes. In some case reports, isolated inguinal node
metastases are also described [9-12]. The exact mechanism of this route of
metastasis is still unclear, but the metastatic cells might follow the course
of the round ligament towards the inguinal lymph nodes or follow the iliac
vessels towards the femoral vessels.
According to the International Federation of Gynaecology and Obstetrics (FIGO),
EOC with lymph node metastases is classified as FIGO stage IIIA1 [13]. This
significant upstaging is reflected in the need for adjuvant treatment. While
patients with cancer confined to the ovaries (FIGO stage I) do not require
adjuvant chemotherapy, patients with EOC FIGO stage III require additional
treatment. Therefore, the detection of lymph node metastases is of utmost
importance in perceived early stage disease.
In case of a clinical early stage ovarian cancer, standard-of-care is a staging
laparotomy including bilateral pelvic and para-aortal lymphadenectomy [14].
There is 14% (range 6.1-29.6%) chance of finding lymph node metastases [15].
The incidence is higher in the grade 3 tumours (20.0%) and the serous
histological subtype (23.3%). Whereas in grade 1 and mucinous tumours this is
respectively 4.0% and 2.6%. By removing a greater number of lymph nodes, the
detection rate for metastases rises [16,17]. Although complete pelvic and
para-aortic lymphadenectomy is standard-of-care, radical lymphadenectomy has
been associated with serious morbidity and this is a major reason for the
difference in the extent of lymph node dissection between centres [12,18-21].
By resecting only the SLN, significant reduction of morbidity and mortality can
be obtained in comparison with the standard-of-care. SLN surgery is based on
the concept that, if the SLN has no malignant cells, the likelihood that other
lymph nodes are affected is reduces to almost non-existent. This means that, at
least theoretically, a radical lymphadenectomy could be omitted and thus the
associated morbidity and potential mortality. The SLN technique has been proven
to be effective in other cancers such as breast cancer and malignant melanoma.
In the gynaecological field it has been shown to be effective in vulvar cancer.
Several SLN studies have been conducted in patients with ovarian cancer with
promising results, as summarized in Table 1 [22].

2.2 Rationale
As stated, the goal of utilizing SLN in early-stage EOC surgery is to reduce
patient morbidity while obtaining optimal oncological outcomes. By resecting
only the SLN, the patients would be spared from radical lymphadenectomy,
reducing short and long-term complications.
As summarized in Table 1, most studies utilize 99mTc and blue dye to visualize
the SLN. Although detection rates are good with these techniques, they have
major disadvantages. 99mTC is an isotope, as such it exposed the patient to an
irradiation dose. Although total dosage is limited, eliminating isotopes in
surgery would reduce the potential harm for the patient and the medical staff
during surgery. Furthermore, the process to produce and administer 99mTC is a
costly and resource-intensive procedure, requiring the cooperation of nuclear
medicine, radio-pharmacy and logistics [34]. As such, reducing the need for
99mTc would benefit the patient, medical staff and the healthcare system in
general by reducing costs. Blue dye such as Patent Blue is often used for the
detection of SLN. However, it also has major disadvantages. Firstly, it
potentially occludes the entire operation field because of dissemination of the
dye further than the SLN. Without optimal visualisation of the anatomy, the
surgeon can expect more difficult dissection. Secondary, blue dye can cause a
severe allergic reaction, leading to anaphylactic shock in up to 2% of patients
[34].
Magtrace® is a brownish ferromagnetic substance capable of identifying the SLN.
This novel technique has already been extensively researched in breast cancer
and proven to be non-inferior to 99mTc with blue dye [35]. These promising
results led to licensing in the European Union. In this trial, we wish to
examine the potential of this technique in EOC, eliminating the disadvantages
of 99mTc and blue dye. However, this is still a pilot study with unknown
efficacy in EOC. Therefore, in order to minimize potential harm to the patient,
we co-administer 99mTc. This has been deliberately chosen due to the extensive
literature concerning this sentinel mapping technique (see Table 1). If the
efficacy of Magtrace would prove successful, the ultimate goal is to omit 99mTc
in further studies and use Magtrace® only to identify the SLN.
In this pilot study, we will include two study arms. One in primary staging
laparotomy, the other one in secondary staging laparotomy. The rationale of
these two arms is based on the clinical practice, were surgeons not always
suspect malignancy before resection of the adnexa. In case of a primary staging
laparotomy the diagnosis of malignancy is based on a frozen section of the
resected adnexa, followed by the sentinel node technique during the same
procedure. On the other hand, in some cases early stage EOC is only diagnosed
after the primary surgery, when the surgeon resects the ovary with the
suspicion of benign disease. If the adnexa are already removed before the
diagnosis of malignancy, a secondary staging laparotomy is required and, in
this case, a single step approach for SLN is not feasible. The design of two
study arms in this pilot study allows to compare the efficacy of Magtrace in
native tissue (primary staging laparotomy) with tissue afflicted by previous
surgery (secondary staging laparotomy).

3.1 Primary Objective
• Feasibility of Magtrace® as a tracer in SLN sampling in early stage EOC.

3.2 Secondary Objectives
• Comparison of detection rate between MagTrace® and 99mTc
o In the general cohort
o In primary staging laparotomy
o In secondary staging laparotomy
• Detection of potential adverse effects of MagTrace® and 99mTc
• Relationship between the observed SLN and the actual number of pathological
lymph nodes

This is a multicentre international pilot study.
The total number of participants is limited to 20 individual patients. 10
patients with primary staging surgery for suspect early stage EOC will be
included and 10 patients with secondary staging laparotomy for confirmed early
stage EOC.
The expected time for patient collection is estimated up to two years.
The study design is represented in figure 1. Further elaboration will be
provided in the methods section.

Figure 1: Overview of the study design

By performing the sentinel lymph node (SLN) technique, the surgery is prolonged
with 20 minutes due to the minimum mandatory tracer migration time after
injection. No extra blood samples will be taken, no extra visits, physical
examinations or other tests are necessary. There is no perceived risk of tumour
dissemination by injecting the tracers in the ovarian ligaments. Adverse
allergic reactions to radiopharmaceuticals like 99mTc are rare with severe
reaction only in 1-6/100,000 patients [34]. Magtrace® is registered for marking
sentinel lymph nodes after interstitial (into the tissue) injection and to be
detected with the Sentimag® device. When similar material to that used in
Magtrace® has been injected directly into the bloodstream (intravenously), the
following undesirable effects have been reported [36]: (<2%) - pain at the
injection site, vasodilation, paraesthesia. (>=0.1% to <1%) - asthenia, back
pain, injection site reactions, chest pain, nausea, vomiting, headache, taste
changes, itching, rash, inflammatory response (localized redness and swelling)
with intradermal injection. (>=0.01% to <0.1%) - Hypersensitivity and
anaphylaxis, hypertension, phlebitis, hyperesthesia, anxiety, dizziness,
convulsion, parosmia, dyspnoea, increased cough, rhinitis, eczema, urticaria.
However the side effects are only reported with injection into the blood, in
our study design injection will be in the lymphatic system.

Low risks for participating patients, magtrace and 99mTc are registered for SLN
mapping. Benefit, for individual patient is low. However for future patients
this novel technique might help ommit a lymphadenectomy.