Management of prostate cancer and patient prognosis depends on the stage of the disease which, in turn, depends on whether the tumor has extended beyond the capsule, whether regional or distant lymph nodes are involved, and whether bony metastases are present. Though traditional imaging modalities are not very helpful in determining nodal involvement, immunoscintigraphy has been recognized as having success in this area. Here, the authors report on the use of capromab pendetide for detection of nodal metastases in the prostate cancer patient.
Prostate cancer has an annual incidence of about 334,500 and a
mortality rate of about 41,800.1 Management of the disease and
prognosis depends on the stage of the disease, which, in turn,
depends on whether tumor has extended beyond the capsule, whether
regional or distant lymph nodes are involved, and whether bony
metastases are present. Existing methods of staging include digital
rectal examination, measurement of prostate specific antigen (PSA)
levels, transrectal ultrasound, computed tomography (CT), and
magnetic resonance imaging (MRI). All are of some use in examining
the prostate, but none are very helpful in determining whether
regional or distant lymph nodes are involved.2
The radionuclide bone scan is the procedure of choice when
looking for skeletal metastases.3 In late 1996, capromab pendetide
(ProstaScint®) was approved by the U.S. Food and Drug
Administration (FDA) for routine clinical use in detection of nodal
metastases in prostate cancer patients. It was developed by Cytogen
Corporation (Princeton, NJ) as a murine whole antibody toa 100
kilodalton glycoprotein foundon the surface of both normal and
abnormal prostate epithelium-the prostate specific membrane antigen
(PSMA), which is very different from PSA. 0.5 mg ofthe antibody, is
labeled to 5 millicuries of Indium-111 chloride for imaging
Evaluation of capromab pendetide (clinical
Cytogen Corp. conducted several multi-institutional trials from
1991 to 1996, in a total of 224 preoperative and 259 postoperative
patients. In the preoperative group there were 190 (85%) positive
studies, out of which 76 (40%) had only prostate or periprostatic
abnormality, 83 (44%) had extraprostatic involvement within the
pelvis, and 31 (16%) had scintigraphic evidence of extrapelvic
In the postoperative group there were 187 (72%) positive
studies. Fifty-seven patients (31%) had only prostate or
periprostatic abnormality. Fifty-five (29%) had extraprostatic
involvement within the pelvis, and 75 (40%) had scintigraphic
evidence of extrapelvic disease.
Capromab pendetide use is generally indicated in two groups of
1) Those with a new diagnosis of prostate cancer with high risk
of pelvic metastases.4 These are patients with PSAs of greater than
10 ng/mg and/or high Gleason histopathologic classifications
(>7). As compared with histopathology, the sensitivity of
capromab pendetide imaging ranged from 52 to 62% and the
specificity was 72 to 96% in detecting pelvic lymph node
metastases.5,6 This compares favorably with the 10% and 15%
sensitivity of CT and MRI, respectively. Another study reported
that CT, MRI, and ultrasound had a combined sensitivity of 20% and
specificity of 68% compared with 75% sensitivity and 86%
specificity of capromab pendetide.7
2) Those with suspected occult recurrent or residual disease.4
These are patients with occult rises of PSA post-operatively. In
the prostatic fossa, two different studies found a specificity of
77% and 35%, and sensitivity of 49% and 71% using histopathological
diagnosis as the gold standard.5,5 Another study found capromab
pendetide scans to be superior to positron emission tomography. The
positive predictive values for capromab pendetide and positron
emission tomography were found to be 60% and 33%, negative
predictive values were 75% and 29%, and sensitivity 86% and 17%,
Capromab pendetide scans do not reliably detect skeletal
lesions. This may be because only about 44% of bony lesions express
PSMA.10 A radionuclide bone scan should therefore be performed
prior to a capromab pendetide scan to exclude skeletal
In clinical trials, pelvic and abdominal lymph nodes often were
visualized scintigraphically. These nodes generally were not
confirmed histopathologically, but the incidence of these findings
closely matches autopsy data.11 The most common nodes were found in
the periaortic, external, and internal iliac chains.
Two acquisition protocols for prostate immunoscintigraphy using
capromab pendetide are currently in use. The first uses single
photon emission computed tomographic (SPECT) imaging of the pelvis
performed about 30 minutes post-injection. SPECT data is gathered
over 360 degrees in six degree intervals, with 20-second sampling
at each stop. A large field of view gamma camera, with a parallel
hole, medium energy collimator is used. These blood pool images are
essential in order to distinguish normal vascular activity from
possible nodal metastases. The patient returns to the department
three to five days later, when whole body planar and SPECT imaging
of the abdomen and pelvis is performed.
The second protocol saves camera time and obtains a better
comparison of the blood pool and antibody images. In this method
the patient is not imaged on the day of injection. Instead, on the
third or fourth day after injection, the patient's red blood cells
are labeled by a standard in vivtro technique with technetium-99m
(Tc-99m). Whole-body planar imaging, followed by SPECT imaging of
the abdomen and pelvis, is performed with simultaneous image
acquisition by the camera using both Tc-99m and In-111 windows.
Normal uptake in the liver, spleen, and bone marrow is observed on
the antibody scan. If there is a lot of activity in the colon, the
patient may have to be recalled for another set of images following
administration of a cathartic. Alternatively, the patient may be
routinely prepared with a cathartic prior to the study. If desired,
subtraction and/or co-registration techniques may
Adverse effects were reported in 4% of 529 patients in the
trials who received a single dose of capromab pendetide.8 The most
common adverse effects were elevated bilirubin, hypertension, and
hypotension, each of which had an incidence of 1%. Elevated liver
enzymes and local reactions at the injection site were experienced
in less than 1% of the patients. Almost all patients who
experienced adverse effects had mild and reversible symptoms.
Human antimouse antibodies
Because capromab pendetide is a murine antibody, there is a
possibility of the development of human antimouse antibody (HAMA)
after a single injection, which can reduce the sensitivity of the
study if a second injection of a murine based antibody is made.
Twenty of 239 study patients (8%) developed HAMA after a single
dose of capromab pendetide, but after repeat infusions, the
incidence was 5 of 27 (19%).8 HAMA levels often fall to negligible
levels in a few months. Before a patient undergoes a repeat
capromab pendetide scan, his HAMA level should be determined.
The estimated total body absorbed dose from the 111-In-capromab
pendetide scan is around 0.14 mGy/MBq, and the effective dose is
0.25 mSv/MBq when scanned with 185 MBq (5 mCi) of 111-In labeled to
0.5 mg of capromab pendetide.12 If activity passing through the
gastrointestinal tract is also taken as a source, the effective
dose is 18% higher. The liver is the critical organ here, receiving
an absorbed dose estimate of 1 mGy/MBq. These doses are similar in
magnitude to those from other whole antibody studies such as
OncoScint®, which has a total body dose of 0.15mGy/MBq and an
effective dose of 0.23mSv/MBq.12
Examples of pelvic and extrapelvic metastases and recurrences
are illustrated in figures 1-3.
Common causes of false positive studies include colostomy,
degenerative joint disease, abdominal aneurysms, post-operative
bowel adhesions, and local inflammatory changes associated with
inflammatory bowel disease, surgery or radiation.13
Treatment of prostate cancer depends on the stage of the
disease. In general, curative treatment is only offered to those
with organ-confined disease. However, clinical staging often is
inaccurate, and a combination of several methods is optimal for
staging. PSA levels are only a rough indicator of the extent of
disease and cannot be used for staging purposes. The PSMA detected
by capromab pendetide is separate from PSA, and the expression of
PSMA rises with dedifferentiation of the tumor.14 Unlike PSA, PSMA
is not down regulated by hormonal therapy,15 and so it is possible
that low PSA levels do not necessarily signify tumor reduction.16
Transrectal ultrasound is about 70% accurate,17 but is applicable
only for imaging of disease localized to the prostate bed. CT and
MRI are not useful for staging, as they provide only gross anatomic
information. Extensive lymph node dissection could give the
necessary information, but the associated morbidity limits its
It is important to identify the presence of extrapelvic disease
in both pre-operative and post-operative patients, as this disease
would be outside the usual surgical field or the usual radiotherapy
treatment portals. It has been shown recently that in
post-operative patients with occult disease demonstrated by only
rising PSA levels, those who had no scintigraphically demonstrable
disease outside the planned radiation field had a better response
to radiation (significant drop in PSA) than those with
scintigraphic evidence of disease outside the planned radiation
Researchers also have tried monoclonal antibodies against
prostate acid phosphatase19 and PSA19,20 to image metastatic
involvement from prostate cancer, but these lacked sensitivity and
had high incidences of HAMA formation (up to 50%),21 compared to a
much lower incidence with capromab pendetide.
Capromab pendetide scanning can demonstrate evidence of
metastases of lymph nodes, both in the pelvis and outside, in a
pattern and incidence similar to available autopsy data. Knowledge
of the presence or absence of lymph nodal metastases helps in
management decisions in the high risk pre-surgical patient, as well
as the post-surgical patient being considered for radiotherapy.
Further investigation should be able to substantiate the important
contribution that capromab pendetide imaging is making to
management decisions in patients with prostate cancer. AR
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Dr. Sinha and Dr. Freeman are with the Department of Nuclear
Medicine at Montefiore Medical Center of the Albert Einstein
College of Medicine in Bronx, NY.