NOdal METastasis in high risk Endometrial Cancer (NOMETEC): detection methods and the prevalence of lymph node micrometastasis

Endometrial cancer is the most common gynaecological malignancy in
industrialized countries. The disease has a relatively good prognosis because
most patients (75%) present early with complaints about postmenopausal
bleeding. Although the mortality rate is rather low compared to other
malignancies; still, yearly an estimated 9000 women die of endometrial cancer
in Europe [1]. Disease related mortality is the result of distant metastasis
and recurrent disease.

The prognosis of endometrial cancer patients depends on the tumour stage,
histological differentiation grade and histological type; moreover it depends
on the woman*s age and the therapeutical possibilities [3,4].

Involvement of the lymph nodes has been proven to be one of the most important
prognostic factors in most other malignant tumours. The lymphatic drainage
routes of the uterus are complex and the evidence on lymphatic spread of
endometrial cancer is scarce.
Current non-invasive imaging techniques are restricted in their ability to
detect metastatic lymph node spread. On the other hand, the benefits of
invasive surgery like a complete lymphadenectomy as part of the routine staging
procedure remain controversial, given the potential morbidity [10,11].

There*s an ongoing discussion about the (primary) surgical treatment of
endometrial cancer. Standard treatment for all patients consists of total
hysterectomy, bilateral salpingo-oöphorectomy, peritoneal cytology and lymph
node palpation/assessment. The recently revised national guideline clearly
recommends a systematic lymfadenectomy in cases of clear cell and serous
papillary endometrial carcinoma. Furthermore, the authors point out the actual
risk of extra uterine disease in type I grade 3 tumours, implying that
lymphadenectomy would be reasonable option in this group of patients [7, 8, 9].
Therefor we need to understand more about the routes of nodal spread to truly
tailor surgical treatment and use targeted adjuvant therapy. Thus potentially
increasing quality if life as well as survival of these patients.

Lymphatic mapping with the sentinel node procedure has emerged as an
alternative to systematic lymphadenectomy. The technique is widely used in
cases with breast cancer and melanoma (12, 13), while it is also used in cases
with vulvar or cervical cancer (14). Burke e.a was the first to study the
sentinel node procedure in endometrial cancer patients in 1996 [15]. So far,
there*s an ongoing dicussion about which site of injection would be most
feasible: cervical vs. submucosal per hysteroscopy vs. subserosal per
laparoscopy or -tomy [16-26].

An estimated 20% of the patients with high risk endometrial cancer have lymph
node involvement. Though current diagnotic work up and treatment guidelines
don*t seem to focus enough on the actual possibility of lymphatic spread. A
surgical-pathological study, performed by the US Gynecologic Oncology Group
(GOG) provides the most reliable data on the relationship between the FIGO
stage of the tumour, the myometrial invasion and the presence of lymph node
metastasis. It has been proven that -among patients with lymph node metastases-
50% have pelvic LNM only, 30% have both pelvic and para-aortic metastases and
20% have para-aortic LNM only [27]. A estimated 50% of all para-aortal
metastasis is situated in the high para-aortal regions. This is probably the
result of various lymph drainage routes of the uterus, wich would explain the
difference in sentinel node detection after each injectionmethod [16-26].

There*s not enough evidence on the prevalence and clinical relevance of
para-aortal metastasis. It is unclear weather a systematic pelvic and
para-aortal lymfadenectomy up to the level of the v. renalis would improve the
disease free survival because there*s a lack of reliable prognostic data [28].
Finally, not only are we interested in the clinical significance of the
location of nodal involvement, but we also wish to know the extent of
metatasis: macroscopic vs. microscopic.

Up till now, only the presence of lymph node macrometastasis has therapeutical
consequences. But, detailed pathological study of a lymph node biopsy with
ultrastaging and immunohistochemical or PCR analysis can identify lymph node
micrometastases (measuring 0.2mm - 2mm) that conventional methods would
identify as negative for metastatic disease. The relation between
micrometastases and the risk of recurrence and prognosis has been demonstrated
in an increasing number of malignancies including breast cancer, vulvar cancer,
gastric cancer, oesophageal cancer, colon cancer, prostate cancer and melanoma,
suggesting that micrometastases should be an indication for adjuvant therapy.

Pushing the limits of diagnostic possibilities, we need to gain more insight in
the clinical consequences of micrometastasis and isolated tumour cells [29,
30].

(References are listed in the research protocol!)

OBJECTIVE NOMETEC PART I: "Mapping the lymphatic drainage of the uterus: a
feasibility study of the sentinel node procedure"

Our aim is to find out which out of two injection methods with technetium
labelled nanocolloid is the best to describe the lymphatic drainage routes of
the uterus:
1. SMI: sub-mucosal injection after hysteroscopy
2. SSI: laparoscopic/laparotomic sub-serosal (fundus) injection.
In addition, we aim to learn which technique is most accurate and/or feasible
for sentinel node mapping in endometrial cancer.

OBJECTIVE NOMETEC PART II: "Nodal metastases in high risk endometrial cancer
(NOMETEC): detection methods and the
prevalence of lymph node micrometastases"

The feasibility study (NOMETEC PART I) will result in the proposal of either
SMI or SSI as the preferred method for lymph node detection. The SN detection
should be possible in at least 80% of patients.
The next step in our investigation is to find out the correlation between
Sentinal Node (SN) involvement and involvement of other pelvic and para-aortal
lymph nodes in high risk endometrial cancer patients.
Finally, we are interested in the feasibility and reliability of the OSNA CK19
test as an intraoperative method to diagnose lymph node macro- and
micrometastasis in sentinel nodes.

The study is a multicenter cross-sectional diagnostic intervention study,
consisting of two sub-studies. Patient enrolment starts medio 2011 and will
take place in the University Medical Center Maastricht, the University Medical
Center Utrecht and the Diakonessenhuis in Utrecht.

NOMETEC PART I is a feasibility study, investigating two methods for sentinel
lymph node detection and drainage system visibility in patients suspicious for
endometrial cancer, undergoing hysteroscopy and laparoscopic or laparotomic
hysterectomy. Both methods will be used in all patients. The methods will be
used independent of each other: the second method will be conducted without
knowledge of the results of the first method. PART I will result in the
proposal of either SMI or SSI as the preferred method for lymph node detection.
The SN detection should be possible in at least 80% of patients.

The next step in our investigation is to find out the correlation between
Sentinal Node (SN) involvement and involvement of other pelvic and para-aortal
lymph nodes in a group of high risk endometrial cancer patients (NOMETEC PART
II). Based on several characteristics of the patients and the tumour, the risk
of lymph node involvement is computed. Among these patients approximately
15-20% has lymph node involvement. The question is whether SN involvement
further improves the prediction of concurrent lymph node involvement in
addition to characteristics such as tumor grade, histological tumour type,
myometrium invasion and age. If so, this may result in a better selection of
patients for adjuvant therapy and/or lympadenectomy, a procedure with
relatively high rates of morbidity.

The determinant is whether information about SN involvement improves the
prediction of lymph node involvement The outcome is lymph node involvement
determined in lymph nodes obtained through lymphadenectomy and histologically
examined (gold standard).
There will be several cut-off points used for defining whether a SN is
malignant: 1) macrometastasis, 2) micrometastasis, 3) isolated tumour cells.
Different pathological tests will also be explored.

As the diagnostic work-up and surgical treatment will be carried out according
to the national guideline, complications during or after surgery will not be
considered as *research risk*.
The administration of the radioactive tracer 99m Tc-nanocolloid for the
sentinel node procedure has been widely experienced and investigated in other
tumours. Adverse effects or complications have been proven to be very rare.
Moreover, the dosage has been approved by the radiological health and safety
officer of the Diakonessenhuis in Utrecht.
The extra burden for the patients, participating in this study, would consist
of the injection with the radioactive tracer 99m Tc-nanocolloid and a
lymfoscintigrafic examination respectively 30 minutes and 2 hours after the
injection. The injection will be performed under adequate anaesthesia.