De toepassing van nucleaire beeldvorming voor de detectie en karakterisatie van primair prostaatcarcinoom bij patiënten met behulp van 99mTc-Tricine/TPPTS/HYNIC-Aca-Bombesine(7-14) SPECT/CT

Prostate cancer is one of the most common causes of cancer in men and a common
cause of morbidity and death in the world. In order to determine the most
optimal treatment of prostate cancer, the disease stage at primary diagnosis
has to be established. On the basis of clinical parameters it is decided if
99mTc-methylene diphosphonate bone scintigraphy and/or a pelvic lymph node
dissection have to be performed in order to detect prostate cancer metastases
in the most likely places, i.e. pelvic lymph nodes and bone.
In non-metasized patients a calculation is made on the basis of their
serum PSA, histology and clinical tumour if organ-confined disease or
capsular-extension/seminal-vesicle-invasion can be expected. For the latter it
is more likely to benefit from radiotherapy to the prostatic region than from a
surgical radical prostatectomy. For the patients with organ-confined disease,
both treatment modalities are equally effective. The sensitivity of CT and MRI
is insufficient for routine application in staging of the primary tumour.
Nuclear imaging techniques like positron emission tomography (PET) or
single photon emission computed tomography (SPECT) could improve detection of
prostate cancer, but current non prostate cancer specific radiotracers like
11C/18F-choline, 11C-acetate, 18F-fluorodeoxyglucose or the prostate cancer
specific 111In-capromab-pendetide are lacking in accuracy, hereby limiting
clinical application.
Antigens (over)expressed in prostate cancer, but sparse in normal
tissue, can be used for antigen-targeted diagnostic applications. Preclinical
and clinical studies where new antibody-based or peptide-based substances are
tested for antigen targeted imaging of prostate cancer have shown promising
results. One such interesting peptide receptor that is overexpressed in primary
and metastatic prostate cancer is the gastrin-releasing peptide receptor (GRPR)
or bombesin (BN) receptor. GRPR is normally found in non-neuroendocrine tissues
of the breast and pancreas and in neuroendocrine cells of the brain,
gastrointestinal tract, lung and to a small extent in prostate. Upon binding
with the gastrin-releasing peptide or a bombesin-like peptide, the receptor
effects a wide range of biological responses[20, 21]. in addition to
overexpression in prostate cancer, GRPR is also overexpressed in several other
types of cancer, like breast, lung, ovarian, renal and gastrointestinal cancer.
Besides the preclinical and clinical use and evaluation of
radiolabelled BN-like peptides for nuclear imaging of various types of cancer,
several BN analogues have also been used as antagonists or carriers to deliver
drugs, radionuclides and toxins specifically to GRPR positive cancers in order
to inhibit tumour growth, induce tumour regression or cause cell death.
In our center we have developed
99mTc-Tricine/TPPTS/HYNIC-Aca-Bombesin(7-14) (from here on: 99MTc-HABN) in a
cooperation project on bombesin imaging between the Medical Isotopes Research
Center, Peking University, Peking, China and the Department of Nuclear Medicine
and Molecular Imaging (NMMI) at the University Medical Center Groningen. Shi et
al. (Peking University) has already published on a comparable
radiopharmaceutical for its preclinical evaluation in human colon cancer
xenograft models [49]. One of the radiochemists that worked on 99MTc-HABN in
Peking is now working here at the department of NMMI as part of the cooperation
project. In vitro experiments have shown excellent uptake of the tracer in
human prostate cancer cells. In vivo experiments in human prostate cancer
bearing nude mice have shown high uptake in the tumour. Results will be
published in 2010.
Clinical evaluation is the logical next step to be taken to implement
GRPR targeted nuclear imaging in clinical practice for tumour staging and
evaluation of response to therapy. Different patient groups will be studied in
different phases. First, we propose on the application of nuclear imaging for
detection and characterization of primary prostate cancer in patients with
99MTc-HABN SPECT combined with computed tomography (CT) for anatomical
co-registration (SPECT/CT). As this is a *first in men* study, the heart-rate
and blood-pressure of the first five patients will be monitored during the
first hour after injection. If no significant changes (>15% change in
heart-rate, >15 mmHg change in systolic and/or diastolic blood pressure) are
seen in blood-pressure or heart-rate, the monitoring can be left out of the
protocol for the other patients.
If 99MTc-HABN SPECT/CT proves useful for detection and characterization
of primary prostate cancer, it could have other diagnostic implications like
SPECT-guided biopsies of hot-spots after repeated negative prostate biopsies in
patients with an elevated serum PSA (common problem). Other possible uses of
99MTc-HABN SPECT/CT could be therapeutic; e.g. planning for nerve-sparing
radical prostatectomy in prostates with limited uptake of the tracer, more
accurate planning for brachytherapy or guidance of intensity modulated
radiotherapy, with a higher radiation dose to areas with elevated uptake of the
tracer. Also, 99mTc-HABN SPECT/CT might be a useful technique for detection of
lymph node or bone metastases of prostate cancer. Intra-operative near-infrared
imaging using the same target could be useful for real-time determination of
radical tumor resection.
.

Primary Objectives:
a. Optimization of the 99MTc-HABN SPECT/CT scanning protocol in the first 5
patients (Phase 0).
b. Detection and characterization of primary prostate cancer (tumor uptake and
tumor-to-background ratio) in patients with 99MTc-HABN prior to a radical
prostatectomy, Comparison with histology and clinical parameters (Phase 1).
Phase 0 patients (5) and Phase 1 patients (15), a total of 20 patients.
c. Pharmacokinetics of the radiopharmaceutical will be determined in serum that
is obtained via an arterial canula at several intervals (first 5 patients).

Secondary Objective(s):
Monitoring of heart-rate (with puls-oxy-meter) and blood-pressure after
injection of 99MTc-HABN. Documentation of reported side-effects.

The current study is an imaging study in which the 99MTc-HABN SPECT/CT is
studied for its ability to detect and characterize primary prostate cancer in
patients scheduled for a radical prostatectomy. Results of the SPECT/CT are
compared to clinical parameters and histology. All patients (20) have been
scheduled for a radical prostatectomy (main inclusion criterium) which is part
of normal prostate cancer treatment. The patients will undergo a combined
SPECT/CT. The scans are the only procedures patients will be submitted to as
part of the study. In the first 5 patients an extended SPECT scan will be made
to determine the optimal scanning protocol. When this has been determined, the
remaining 15 patients will be submitted to the optimal SPECT scan protocol. In
the first 5 patients pharmacokinetics of the radiopharmaceutical will be
determined in serum that is obtained via an arterial canula at several
intervals.

As this is a *first in men* study, the heart-rate and blood-pressure of all
patients will be monitored during the first hour after injection. Significant
changes (>15% change in heart-rate, >15 mmHg change in systolic and/or
diastolic blood pressure) and other reported side-effects will be documented
for all patients.

After the SPECT/CT scan, the study has ended for the patient. After the scan
the patient will undergo the radical prostatectomy, which will not be postponed
for study purposes. Normal waiting time for such a treatment is 4 to 6 weeks.
This should be enough time for inclusion, for patients to decide on their
participation and for performing the scan(s).

Also, the results of the first 5 patients will be reported to the local ethics
committee before proceeding to scan the remaining 15 patients.

Histologic examination of prostate cancer tissue after prostatectomy is part of
normal tissue analysis; number, position, size and Gleason score of each cancer
lesion will be documented. Analysis will however be extended by introducing
Ki-67 staining (proliferation marker) and GRPR staining (bombesin receptor).
This will have no clinical implications and can be done with the prostatectomy
specimen that was resected as part of normal clinical practice.

The results of the SPECT/CT will be compared with histology results and
clinical parameters (serum-PSA, Gleason-score and clinical tumour stage).

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Justification: Currently, there are no imaging techniques available for
detection/staging of primary prostate cancer. Prostate cancer is diagnosed on
the basis of elevated serum levels of PSA, rectal examination and random
biopsies of the prostate. Octant biopsies of the prostate are false-negative in
30% of cases and will have to be repeated when prostate cancer is expected.
99MTc-HABN SPECT/CT might be a technique that is both able to detect
intra-prostatic hot-spots, thereby guiding prostate biopsies. 99MTc-HABN
SPECT/CT might also be able to stage prostate cancer and, based on its
findings, therapy can be amended (e.g. planning for nerve-sparing radical
prostatectomy in prostates with limited uptake of the tracer, more accurate
planning for brachytherapy or guidance of intensity modulated radiotherapy,
with a higher radiation dose to areas with elevated uptake of the tracer).
Also, 99mTc-HABN SPECT/CT might be a useful technique for detection of lymph
node or bone metastases of prostate cancer. Intra-operative near-infrared
imaging using the same target could be useful for real-time determination of
radical tumor resection.
Benefits: Since this is a new technique and it has not proven to be of benefit
for local staging of prostate cancer, there is no direct benefit for this group
of patients. Results of this study will not be used for treatment decision.
Risk Assessment:
Risks due to placement of arterial and venous canula: the formation of a
haematoma is minimal. The placement of the canula is painful, however minimal.
Risk due to injection of 99MTc-HABN: please refer to the IMPD pages 1 to 10 for
a detailed description of the substance, toxicology and human exposure of
radiolabelled bombesin-like peptides. In short, no adverse effects have been
reported in prior studies with similar compounds, so no adverse effects are
expected.
Risks due to exposure to radiation: the use of CT and gamma-photon emitting
isotopes means the exposure to radiation. Because of the potential hazards of
radiation, guidelines for the exposure of volunteers are specified in *Besluit
Stralingsbescherming Kernenergiewet (BSK2000)*, according to the guidelines of
the International Commission of Radiological Protection (ICRP 62, 1992).
A CT of the prostatic region (pelvis) will be performed from the upper iliac
crest to the pubic bone. A SPECT scan of the prostatic region will be performed
after injection of 500-700 MBq of 99MTc-HABN. The first 5 patients will undergo
multiple SPECT scans, this won*t give extra radiation, except for a second CT
at the 20 hour time-point.
Calculation of radiation: 99MTc-HABN is expected to deliver a radiation dose of
4.5E-3 mSv/MBq, at a maximum dosage of 700 MBq this will come down to 3.2 mSv.
CT of the prostatic region will be 1.5 mSv. Leading to a total of 3.2 + 1.5 =
4.7 mSv per person. (the first 5 patients will have 2 CT scans and therefor 3.2
+ 1.5 + 1.5 = 6.2 mSv per person)
The amount of radiation falls into category II-B (1-10 mSv) of the ICRP-62
guidelines (Normal background radiation per person per year is 2-2.5 mSv). This
guideline states that medical research with category II-B exposure should be
aimed directly to improvements in the diagnosis, cure or prevention of disease.
In the first subparagraph of this paragraph and throughout the protocol the
necessity of this study is pointed out. The benefit of a good diagnostic tool
suitable for detection of prostate cancer is more than substantial. Formation
of a second primary malignancy due to radiation because of SPECT/CT procedure
is possible, but unlikely. Moreover, since most patients in this group are
elderly people, the latency of secondary malignancies (15-30 years) will make
it very unlikely to cause any problems.
Burden:
For group 1: 5 patients in which an extended SPECT protocol is applied: To
minimize patient burden, all patients will be submitted to the urology ward on
a Tuesday. The scanning protocol can be started on Tuesday, and 20 hours later
on Wednesday the last scan can be performed. After the last scan the patients
will return to the urology ward and being prepared for surgery (radical
prostatectomy), which is always performed on Wednesday.
For group 2: 15 patients with the definitive SPECT protocol: one visit to the
department of NMMI or depending on the planning patients can be submitted to
the urology ward. Scanning time point is uncertain at this moment.
Another burden is the minimally painful placement of the venous canula (20
patients) or the arterial canula (5 patients) prior to the SPECT scan.
Group relatedness: the group of patients participating in this study is the
same as the target-group (prostate cancer patients).