The use of indocyanine green for accurate sentinel node detection and removal in a group of high-risk nodal metastasis prostate cancer patients
To optimize and improve the sentinel node procedure in men with prostate cancer

Presence of metastasis in the first tumor draining lymph node(s) (referred to
as
sentinel node) in the pelvic region is considered a strong predictor of
treatment failure in patients with prostate cancer [Fujisawa, 2008 #2].
Postoperative histopathological examination of tissue samples obtained during
surgery is the *golden standard* to assess the metastatic spread. To obtain
these samples, extensive dissection of the lymphatic tissue is required, a
procedure that can lead to post-operative complications such as lymphoceles,
injuries to the obturator nerve and/or the ureter, and lymphedema of the lower
extremity [Heidenreich, 2007 #3]. Moreover, despite an increase in resected
lymph nodes, early sentinel node studies have indicated locations of primary
landing sites outside the extended field in 5-10% of cases.
Surgical pelvic lymphadenectomy can be improved with better surgical guidance
along the (tumor draining) lymphatic ducts towards the (sentinel) lymph nodes
[Jeschke, 2008 #1;Link, 2001 #4;Bader, 2002 #6]. Ideally, an intraoperative
imaging approach enables the surgeon to visualize and excise these sentinel
nodes accurately, which may shorten overall procedure time and decrease
complication levels.
Innovations in lymph node mapping have come mainly from the melanoma and breast
cancer fields [Giuliano, 1994 #7;Morton, 2006 #8]. At present, lymph node
mapping in e.g. the breast is performed with a combination of preoperative
99mTc-labeled nanocolloid injection and intraoperative injection of blue dyes
(e.g. patent blue) for visible guidance [Mariani, 2004 #13].
Preoperative lymphoscintigraphy, using 99mTc-labeled nanocolloidal particles,
has also demonstrated its use in imaging of the sentinel nodes in the prostate
[Warncke, 2007 #15]. The intraoperative translation of the radiocolloid
procedure requires the use of a gamma probe or camera to monitor the transit of
a 99mTc-labeled nanocolloid from the injection site into the sentinel node(s)
(currently used in the clinic at the NKI-AvL) [Meinhardt, 2008 #17;Olmos, 2009
#20]. Unfortunately, the applicability of radionuclide-based intraoperative
detection remains challenging. Ideally an extra visual aid, e.g. blue dyes, can
help guide the surgeon. However, the dynamics of the conventional blue dye
limit
its use in prostate cancer.
Recently, several promising new trials have been published for breast,
prostate,
and gastrointestinal cancer [Ogasawara, 2008 #22;Kusano, 2008 #25] using the
near-infrared (NIR) fluorescent dye indocyanine green (ICG) for intraoperative
fluorescence detection of lymph nodes. In a feasibility study (in breast), the
federal drug administration (FDA) has suggested that a *cocktail* injection of
fluorescent and radioactive agents would be preferable over multiple single
injections [Sevick-Muraca, 2008 #26]. In the preclinical setting we have fully
optimized this approach in a spontaneous mouse model for prostate cancer [van
Leeuwen, 2011 #40].
In the previous version (version 1.1) of this study protocol, we performed a
pilot study using a combination *cocktail* of ICG and 99mTc-nanocolloid
(hereafter referred to as ICG-99mTc-nanocolloid) for sentinel node mapping
during laparoscopic pelvic sentinel node dissection for prostate cancer. Here
we
showed that with ICG-99mTc-nanocolloid we were able to facilitate and optimize
dissection of the sentinel nodes during robot-assisted laparoscopic
prostatectomy (RALP) procedures [van der Poel, 2011 #39]. ICG-99mTc-nanocolloid
allowed preoperative surgical planning and intraoperative optical detection of
the sentinel nodes. Furthermore, it was found that especially when sentinel
nodes were located close to the injection site, fluorescence imaging was useful
as gamma probe detection was hindered due to the background signal coming from
the injection site [van der Poel, 2011 #39]. In addition to this, the
fluorescence signal (which can be detected > 3 months after injection) allowed
us to study the influence of the location of the intraprostatic injections on
the observed lymphatic drainage [Buckle, 2012 #129]. Fluorescence imaging of
the
paraffin-embedded prostate samples suggested that the location where the tracer
is injected is of influence on the observed lymphatic drainage pattern [Buckle,
2012 #129].

The overall goal of this study is to further validate and improve the
sentinel node procedure for prostate cancer using ICG-99mTc-nanocolloid. The
first objective aims at further validation of the sentinel node procedure for
prostate cancer via ultrasound guided transrectal ICG-99mTc-nanocolloid
injection surrounding the primary tumor. To achieve this goal, tumor location
will be determined based on the acquired diffusion weighted MR images.

Secondly, in a subset of 20 patients we would like to study whether we can
improve the identification of lymphatic drainage patters through a preoperative
intraprostatic injection of fluorescein at the start of the surgical procedure.

Tertiary objective: Fluorescence imaging of tracer deposits in paraffin
embedded prostate tissue

This is a non-randomized, open study on the use of ICG-99mTc-nanocolloid to
improve the sentinel node procedure of prostate cancer. The addition of
fluorescence (ICG) to the conventional (99mTc-nanocolloid) sentinel node
procedure allows intraoperative optical detection of the sentinel node thereby
possibly improving the sentinel node procedure as a whole. Fluorescein is used
to visualize tumor draining lymphatic ducts during surgery.

Study population:
A total of 112 patients will be included in this study with localized prostate
cancer.

No special patient preparation is required. Approximately 4 hours prior to
surgery ICG-99mTc-nanocolloid will be injected transrectally under ultrasound
guidance into the prostate tumor as is routinely done for
99mTc-nanocolloid guided sentinel node detection. Patients will undergo
lymphoscintigraphy and a SPECT/CT scan for preoperative planning. To answer the
tertiary objective, 5-10 min prior to surgery, in a subset of 20 patients,
fluorescein will be injected into the prostate. During surgery the resection
will be guided by both the radioactive signature (laparoscopic gamma probe) and
the fluorescent signature (fluorescence laparoscope (Karl Storz Endoscopes)).

Other than intraoperative injection and tracking of ICG (and fluorescein), this
study will not be any different from standard procedures. ICG-99mTc-nanocolloid
will be injected approximately 4 hours prior to surgery. Additionally, in a
group of 20 patients, prior to surgery fluorescein will be injected. Operation
time may be extended by 10-15 min due to the imaging time. It may, however, be
anticipated that the number of resected sentinel nodes, and hence staging, may
be improved after ICG-99mTc-nanocolloid (and fluorescein) injection.
As mentioned earlier, in rare cases oversensitivity (> 1/1.000 to < 1/100
(fluorescein)), nausea, urticarial and anaphylactic reactions (< 1/10.000
(ICG);
> 1/10.000 to < 1/1.000 (fluorescein)) have been reported after intravenous
injection of ICG or fluorescein. Because of the proposed exclusion criteria,
these numbers will be lower within this study. Patients will be monitored up to
24 hours post-surgery.
Conversely, the value of adequate lymphadenectomy could have major results on
the improvement of staging and postoperative outcome of prostate carcinoma
patients.