Prospective randomized multicenter comparison of indocyanine green (ICG)-99mTc-nanocolloid vs. 99mTc-nanocolloid plus an intraoperative injection of ICG for the detection and surgical resection of the sentinel nodes in patients with prostate cancer

Sentinel node (SN) identification was shown to aid in the diagnosis of nodal
metastases in prostate cancer. Since the introduction of lymphoscintigraphic SN
detection for prostate cancer by Wawroschek and collegues [Wawroschek et al.,
Eur Urol 1999] several institutes showed the value of SN for detecting nodal
metastases outside the field of the extended nodal dissection. Despite this
improved diagnosis, SN dissection has not gained widespread acceptance. Several
explanations for the absence of SN detection in daily practice can be put
forward. The false negative rate of SN detection, that is the percent of men
that have lymph node metastases despite a negative SN procedure, ranges between
5 and 15% with a mean op 10% (Table 1). This can be explained by inadequate
drainage of tracer into lymph nodes due to tumor infiltration or lymph tract
blockage by tumor. It can also be explained by the inability to properly detect
and resect the SN(s) during the surgical procedure.
The complexity of lymph drainage for pelvic organs such as bladder and
prostate requires thorough mapping of the draining lymph nodes, such as SN in
both the pre- and intraoperative setting. Classically, this imaging was
performed for penile cancer using lymphangiography [Cabanas, Cancer 1977].
Lymphoscintigraphy was introduced in the 90s of the last century, and later the
introduction of single photon emission tomography complemented with computer
tomography scanning allowed the nuclear mediciny physician to localize the
SN(s) within its anatomical habitat.
For intraoperative detection a gamma probe-based detection method can
be applied. Although highly sensitive, gamma probe detection has a low spatial
resolution and cannot distinguish between the area of interest and the
background signal (coming from the prostate) in case a SN is located close to
the prostate. Since gamma ray detection provides no anatomical detail and blue
dye was shown to be of little value, recently fluorescent dyes (e.g.
indocaynine green (ICG)) were introduced in for intraoperative SN detection
[Polom et al., Cancer 2011; van den Berg et al., J Nucl Med 2013; Jeschke et
al., Urology 2012]. Next to free ICG, we introduced the hybrid tracer
(ICG-99mTc-nanocolloid) combining radioactivity and fluorescence for the
detection of the SN [van Leeuwen et al., J Biomed Opt 2011]. With this hybrid
tracer, in prostate cancer patients we showed that it allowed for both
preoperative SN mapping and intraoperative gamma ray detection using the
radioactive signature of this tracer. In addition, the fluorescence signature
provided intraoperative near infrared (NIR) fluorescence-based detection of the
SN(s) [van der Poel et al., Eur Urol 2011].
As compared to dissection based on the acoustic signal provided by the
gamma probe, NIR-guided SN dissection allowed for more accurate identification
of the individual SN and also provided anatomical information on lymph tracts
[Jeschke et al., Urology 2012]. However, in contrast, the use of the
fluorescent dye alone does not allow for preoperative SN mapping and as such
discriminating SNs from non-SNs (higher-echelon nodes) can become difficult.
Several questions remain on the value of ICG-NIR guided SN
identification. The role of the local tracer injection into the prostate is
more important than previously assumed (J Nucl Med. 2012 Jul;53(7):1026-33.).
Moreover, the additional value of intraoperative ICG-NIR tracing of the ICG
signal over the conventional approach of aboveof gamma signal tracing needs
evaluation. In addition, as well as the role of free ICG versus 99mTc-
nanocolloid bound ICG (ICG-99mTc-nanocolloid) should be evaluated to determine
the value of the tracers. Free ICG more rapidly migrates from the prostate into
both lymph tracts and nodes, but does not accumulate for longer periods into
the nodes. In contrast, the hybrid tracer ICG-99mTc-nanocolloid Nanocolloid is
transported slower throughin the lymph system and like free ICGits parental
compound 99mTc-nanocolloid it accumulates in the SN [Uren, Ann Surg Oncol
2004]. (Uren, Howman-Giles, & Thompson, 2003) Similar to free ICG the
nanocolloid is transported to second tier nodes in case of a saturated SN, as
does nanocolloid bound ICG.
To address these important questions we designed a prospective randomized
multicenter study to compare the hybrid tracer (ICG- 99mnanocolloid-bound
Tc-nanocolloid) and freeto ICG for sentinel node biopsy in prostate cancer as
well as the efficacy of NIR-based guided SN tracing over compared to 99mTc99m
gamma signal tracing will be determined.

Primary Objective(s):
1. Number of positive patients (as determined following histopathological
analysis of the excised nodes).

Secondary Objective(s):
Collection of the below summarized information will provide us an answer to the
following secondary endpoints:
1. What is the role of preoperative SPECT/CT for the identification of SNs
draining from the prostate?
2. Is there a difference between ICG-99mTc-nanocolloid and free ICG in the
optical identification of SNs of the prostate?

Prospective randomized case-control study.

Approximately 4 hours prior to surgery ICG-99mTc-nanocolloid will be injected
transrectally under ultrasound guidance into the prostate as is routinely done
for 99mTc-nanocolloid guided sentinel node detection. Patients will undergo
lymphoscintigraphy and a SPECT/CT scan for preoperative planning. In group 2
the patients will receive an intraprostatic injection 10 minutes prior to the
prostatectomy and sentinel node detection.

Other than intraoperative injection and tracking of ICG, this study will not be
any different from standard procedures. ICG-99mTc-nanocolloid will be injected
approximately 4 hours prior to surgery. It may, however, be anticipated that
the number of resected sentinel nodes, and hence staging, may be improved after
ICG-99mTc-nanocolloid injection. As mentioned earlier, in rare cases
oversensitivity: nausea, urticarial and anaphylactic reactions (< 1/10.000
(ICG) have been reported after intravenous injection of ICG. Patients will be
monitored up to 24 hours post-surgery. Conversely, the value of adequate
staging could have major results on the improvement of staging and
postoperative outcome of prostate carcinoma patients.