By Samuel Kipper, M.D., Pacific Coast Imaging, Irvine, CA
Reprinted from PCRI Insights August 2003 vol. 6, no. 3
Prostate cancer management has advanced significantly over the last decade, most notably with improved methods of risk stratification, which allow for more appropriate treatment selection for individual patients based on their individual prognostic factors. Some of these improvements have come in the field of diagnostic imaging, including ProstaScint® and MRI, and, foremost, the combining of modalities with new image fusion techniques.
Following diagnosis, the determination of the extent of prostate cancer remains one of the most critical issues for both patients and clinicians charged with the selection of appropriate treatment. Distinguishing newly diagnosed patients with confined localized prostate cancer from those whose cancer has spread to the lymph nodes or more distant sites is important since the corresponding therapies may differ radically. For the same reason, distinguishing local residual or recurrent disease from nodal or distant metastases in post-prostatectomy or post-radiotherapy patients is equally important.
Defining the precise extent and location of disease is difficult since existing diagnostic modalities such as MRI and CT often do not detect soft tissue metastases from prostate cancer. There is a significant need for an accurate non-invasive diagnostic tool to detect both the location and extent of the prostate cancer both in newly diagnosed patients and in patients with prostate cancer that recurs after definitive therapy. An accurate staging tool would result in therapy that is appropriate for the location and extent of disease present.
Diagnostic Studies for Evaluation of Prostate Cancer
The distant spread of prostate cancer occurs by both blood and lymphatic routes, especially along the pelvic and abdominal great vessels. Local spread is by direct invasion of the tumor beyond the prostate capsule. Lymphatic or extraprostatic extension of disease occurs in approximately 40% of patients with clinically localized prostate cancer.1 A large percentage of patients with apparently clinically localized prostate cancer prior to surgery are found to have extraprostatic disease when the tissue is examined after surgery.
The initial clinical staging of newly diagnosed prostate cancer relies heavily upon the use of predictive nomograms that have incorporated prostate-specific antigen levels, Gleason scores and clinical stage in an attempt to accurately predict final pathologic stage. On an individual basis, these nomograms are associated with a significantly high false-positive rate.2 Therefore, if patients are suspected to be at an increased risk for metastatic disease at the time of diagnosis based on PSA value or Gleason score, they frequently undergo additional diagnostic imaging studies including bone scans, computed tomography (CT) or magnetic resonance imaging (MRI). The bone scan is quite sensitive for demonstrating metastatic disease in the skeleton; however, bone metastases are generally discovered at a more advanced stage of prostate cancer and less frequently at the time of initial diagnosis (unless the PSA level is greater than 10). Additionally, bone scan findings are nonspecific with frequent false-positive results due to benign causes, such as trauma and arthritis.
The conventional anatomic imaging modalities of CT and MRI frequently understage the extent of prostate cancer, resulting in false negative results which contribute to a significant number of patients with extraprostatic disease undergoing noncurative surgery and suffering from the ongoing progression of disease.3 The detection of nodal metastases with MRI and CT is based on size criteria, with a nodal size of 1.0 cm often used as the upper limit of normal.4 Early metastatic nodal disease from prostate cancer is usually small (<1 cm) and therefore is missed using CT and MRI. Moreover, enlarged nodes with benign processes may be falsely diagnosed as malignant.
In some patients, lymph node status is most accurately assessed by bilateral pelvic lymph node dissection (PLND). This technique is surgically invasive and fails to correctly identify all patients with metastases due to incomplete sampling. PLND has been reported to result in false-negative interpretations in 12% to 33% of patients. Fifteen percent to 50% of pelvic node negative patients may still harbor prostate cancer in more remote upper pelvic or abdominal lymph nodes. Prostate cancer may bypass the conventional area of pelvic lymph node dissection (skip metastases) and extend into the paraaortic, mesenteric and external iliac nodes.5
An additional disease management dilemma arises in patients who develop elevated levels of serum PSA following prostatectomy or radiation therapy. The elevated PSA level is a reliable indicator that the cancer has recurred; however, the important question is whether the cancer has recurred locally in the prostate surgical bed, or fossa, or has spread beyond the prostate fossa. Locally recurrent disease following surgery can be treated with radiation while metastatic disease is usually treated by a more systemic approach. CT and MRI results at the time of PSA rise are almost always negative, since PSA increases may precede clinical evidence of disease by 1-3 years.
Needle biopsy of the prostate fossa is insensitive and, even when positive, only identifies residual or recurrent disease in the prostate fossa; it is unable to evaluate the rest of the body. Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) does not adequately detect local recurrence after radical prostatectomy, due to the low metabolic activity of prostate cancer and interference with normal urinary activity in the bladder.6 PET only has a role in evaluating aggressive advanced prostate cancer. As a result, a more accurate and more sensitive non-invasive test, perhaps used in combination with existing tests, is needed.
ProstaScint Imaging Revisited
In an effort to make critical distinctions between localized and metastasized prostate cancer, In-111 capromab pendetide (ProstaScint) imaging using a SPECT gamma camera has emerged as a promising diagnostic tool for detecting prostate cancer. ProstaScint is a site-specific murine monoclonal antibody that is reactive with prostate-specific membrane antigen (PSMA), a glycoprotein expressed by prostate tissue. It is strongly reactive with both primary and metastatic prostate carcinoma in addition to normal prostate tissue.7 PSMA continues to be expressed in patients with androgen deprivation therapy, but is preferentially elevated with metastatic, poorly differentiated, and hormonally refractory prostate cancer, all situations in which PSA may not be useful.8
ProstaScint received Food and Drug Administration (FDA) approval in 1996 for use as an imaging agent (1) for the staging of newly diagnosed patients with biopsy-proven prostate cancer who are at a high risk for soft tissue metastases or (2) for the restaging of postprostatectomy patients with a rising PSA level. The early clinical studies leading to FDA approval were performed prior to establishing optimal imaging techniques. Specifically, older single-head gamma cameras were used, dual isotope blood pool imaging with fusion was not performed, bowel preps were not routinely administered, imaging beyond two days after injection was not required, and lastly, image fusion with CT and MRI was not yet available. Consequently, the accuracy and predictive values from early reports may actually underestimate the results currently obtained by experienced high-volume imaging centers and experienced nuclear medicine physicians utilizing these newer advanced imaging techniques.
As the clinical experience with ProstaScint grows, additional clinical settings in which ProstaScint can have an impact on patient management have come to be recognized. These include the evaluation of patients with rising PSA levels after radiation therapy, treatment planning for brachytherapy and external beam radiotherapy, and restaging patients with hormone resistant disease.
In one of the original studies, ProstaScint imaging was performed in 152 patients undergoing radical prostatectomy to evaluate pelvic lymph node status.9 The results of these ProstaScint scans were compared to the lymph node pathology obtained from PLND. This study reported that ProstaScint was approximately 70% accurate. Of note, this study revealed that 14 of 25 men (56%) with negative lymph nodes on pathology but positive ProstaScint scans experienced PSA progression following radical prostatectomy. This suggested that the true accuracy of ProstaScint imaging may actually be higher than reported.
Because the value of a diagnostic imaging modality is measured in its potential impact on patient management and health outcomes, it is noteworthy that ProstaScint was found to be the best single predictor of positive lymph nodes in a study population at high risk for nodal metastasis.10 Gleason score, PSA, and ProstaScint results were all fairly good predictive factors when considered separately, but only ProstaScint demonstrated statistically significant, independent evidence for lymph node metastases if used alone. ProstaScint imaging detected lymph node lesions that were not identified by other diagnostic tests and were confirmed to be malignant in 38 patients in addition to revealing malignancy in 12 patients in areas outside the field of surgery.
In a multi-center study comparing ProstaScint imaging to PLND in 51 prostate carcinoma patients at high risk for lymph node metastases, ProstaScint surpassed the combined diagnostic performance of CT, MRI and US with an overall accuracy of 81%.11 Additional data from this study provided evidence of the potential beneficial impact of ProstaScint imaging on health outcomes. Two patients were found to have histologically proven “skip metastases” near the level of the aortic bifurcation, which is outside the conventional location of standard pelvic exploration. Both patients had had previous pelvic lymph node dissections that were pathologically negative, but ProstaScint scans that were abnormal as shown in Figure 1. The investigators noted that because patients who have skip metastases and negative pelvic lymph nodes have been found to later develop distant metastases, ProstaScint imaging was instrumental in detecting metastatic disease early and prompting further investigation.
Figure 1. Whole Body ProstaScint Scan of a Patient with Rising PSA while Undergoing Hormonal Therapy. ProstaScint activity in a left supraclavicular lymph node and in many central abdominal lymph nodes (arrows) indicates a high likelihood of metastatic disease and hormone resistant tumor.
The contribution of ProstaScint imaging to the management of patients with prostate cancer is largely based on its ability to find metastatic disease in lymph nodes that are not pathologically enlarged and, therefore, are deemed to be negative because of the size criteria associated with CT and MRI.9,11,12,13 It should be understood, however, that because ProstaScint imaging has been reported in some articles to have a false positive rate as high as 20%, patients with a low risk of nodal metastases are not appropriate candidates for this type of study. On the other hand, men who have an intermediate to high risk of nodal metastases are considered to be more appropriate candidates.
ProstaScint imaging in the post-prostatectomy patient provides prognostic information regarding which patients are most likely to benefit from salvage radiotherapy to the prostate fossa. Some studies have reported that patients with abnormal ProstaScint uptake in areas outside the prostate fossa are more likely to fail radiation therapy compared to those with negative scans or uptake confined to the prostate fossa.14,15
ProstaScint imaging has also been utilized to provide information used to help design treatment fields and to optimize existing fields for radiotherapy.16,17 ProstaScint has the potential of individualizing treatment fields based on patient-specific scan findings, rather than using a blanket policy or rigid radiotherapy protocol. Co-registration of ProstaScint images with CT or MRI leads to a more precise interpretation and may enhance the role of ProstaScint imaging in radiation therapy treatment planning.17,18
ProstaScint activity in a left supraclavicular lymph node and in many central abdominal lymph nodes (arrows) indicates a high likelihood of metastatic disease and hormone resistant tumor.
ProstaScint Fusion Imaging
Recently, a novel technique called ProstaScint Fusion imaging was developed, initially as an aid in scan interpretation. Early results indicate that this fusion technique can significantly enhance detection of nodal disease, eliminate some of the false positive results from bowel activity, and accurately map the prostate gland for tumor distribution. Fusion imaging combines ProstaScint imaging with CT or MRI imaging and co-registers the images to provide a uniquely detailed fusion image of high diagnostic quality. In order to optimize information obtained from ProstaScint imaging, it is now recommended that all studies be performed with either CT or MRI fusion.
The following is a brief description of the fusion imaging procedure developed at Pacific Coast Imaging. Patients who are referred for ProstaScint fusion imaging with CT or MRI by their physician receive an intravenous injection of In-111 ProstaScint during their first visit. No adverse reactions or side effects are anticipated from the injection. Preparation for the imaging procedure is performed four to five days following the injection and is fairly simple. The only requirements are adequate hydration starting immediately after the injection, an oral bowel prep of magnesium citrate, and a Fleet Enema® on the day before returning for imaging. There is no need for fasting or invasive procedures such as bladder catheters or rectal probes.
Four to five days following the ProstaScint injection, a whole body scan is performed using a dual detector head gamma camera; this process takes about 25 minutes. Scans performed too soon after injection may obscure sites of cancer in the lymph nodes because of excessive activity in the blood vessels.
The whole body scan is followed by a dual isotope single photon emission computed tomography (SPECT) scan of the pelvis and abdomen which takes about 45 minutes to complete. The dual isotope technique, which uses both In-111 ProstaScint and Tc-99mlabeled red blood cells, was developed to take advantage of the labeled red blood cells as an anatomic marker to aid in the localization of lymph nodes and the prostate bed.19 Had this technique been available in early evaluations of ProstaScint, the accuracy of interpretation likely would have been better.
Recent advances in image computer processing techniques have further refined and improved the quality of ProstaScint images presented to the Nuclear Medicine physician for interpretation.
Along with improved image acquisition and processing techniques, greater physician experience with interpretation is another key component leading to improvements in ProstaScint imaging since FDA approval. Finally, multi-modality image fusion with CT and MRI is the most recent and significant advance in ProstaScint imaging, and it has directly led to improvements in study interpretation enhancing the overall accuracy of the test.
In our center, either a non-contrast CT or MRI study of the pelvis is performed immediately following ProstaScint imaging. These studies provide an anatomic reference or framework for fusion with the ProstaScint SPECT images. This is accomplished by post-image acquisition software co-registration (image fusion). Cross-sectional images from the SPECT and CT or MRI are converted into one image set by co-registering these studies with the aid of anatomic landmarks such as bone, blood vessels, and the body surface. The resulting image fusion study combines a functional study (ProstaScint) and an anatomical study (CT or MRI), a combination that provides more information together than either study interpreted separately (see Figures 2-4). When the ProstaScint study demonstrates abnormal lymph node activity, we recommend a diagnostic CT with intravenous and oral contrast agents to help localize abnormal lymph nodes. Although many CT scans fail to demonstrate enlarged lymph nodes, they may reveal numerous normal-sized lymph nodes which can be helpful.
For newly diagnosed patients with clinically localized prostate cancer who are at high risk for pelvic lymph node or seminal vesicle metastases, a ProstaScint/MRI fusion study may be used to determine a patient’s eligibility for definitive local forms of treatment such as radical prostatectomy, cryotherapy, external beam radiotherapy, or brachytherapy. Potential health benefits derived from a positive scan that demonstrates extraprostatic tumor involvement include the avoidance of major surgery and its associated risks and morbidity.
The results of a ProstaScint/MRI fusion study may also potentially alter or adjust radiotherapy plans such as including combining of brachytherapy and external beam radiotherapy (see Figure 2). Additionally, the fusion study may help the radiation oncologist minimize radiation damage to normal tissue, in particular the neurovascular bundles (see Figure 3). For patients who have already undergone definitive therapy with surgery or radiation, the fusion study may be performed with a CT scan instead of an MRI (see Figure 4). In particular, a ProstaScint/CT fusion study is indicated when a post-prostatectomy or post-radiation therapy patient experiences a rising PSA level.
Figure 2. This is a ProstaScint MRI fusion study performed on a patient considering brachytherapy for treatment of prostate cancer (Gleason score of 3+3, PSA level of 9.6). The mage on the left is an MRI through the base of the prostate gland. The image on the right is the same MRI image fused with a corresponding ProstaScint image. Abnormal accumulation of ProstaScint is visualized in the peripheral zones of both prostate lobes. The abnormal ProstaScint activity extends into the neurovascular bundle area and periprostatic tissue on the patient’s right side (red arrow). This patient refused an additional boost of external beam radiation. The PSA level started rising 6 months after brachytherapy.
Figure 3. This is a ProstaScint MRI fusion study performed on a patient considering brachytherapy for treatment of prostate cancer (Gleason score of 4+3, PSA level of 8.5). ProstaScint activity is present in the peripheral zone of the right prostate lobe (red arrow). The neurovascular bundle areas are clear and there is no evidence for extraprostatic activity. Potentially, the radiation dose could be lowered to the neurovascular bundles possibly helping to reduce the potential of developing adverse side effects such as impotency.
Figure 4. This is a ProstaScint CT fusion study performed on a patient with a rising PSA level following radiotherapy. Abnormal ProstaScint accumulation is demonstrated in the seminal vesicles (red arrows on image A) and right pelvic lymph nodes (yellow arrow on image B). This patient’s prostate cancer most likely has spread beyond the prostate gland into the seminal vesicles and pelvic lymph nodes.
In summary, prostate cancer is a unique type of disease where prognostic information gives both physicians and patients opportunities to be selective in making disease management decisions. ProstaScint imaging certainly adds to the information available for patients in certain situations although, as with any imaging technology, it has its strengths and weaknesses. When used in the correct clinical setting, performed in experienced high quality imaging centers, and fused with CT or MRI, ProstaScint is a useful clinical tool, providing definite benefits to the patient. As with any diagnostic tool, it should not be relied upon alone in a vacuum, but can contribute additional important information that patients and their physicians may require to make well-informed decisions regarding their treatment.
Editor’s Note: ProstaScint is a product of the EUSA Pharma
A list of ProstaScint sites, including those with fusion, is located on the ProstaScint website.
Samuel L. Kipper, M.D., medical director of Pacific Coast Imaging in Irvine, CA, is a nationally recognized nuclear medicine physician. Prior to developing Pacific Coast Imaging, he was director of nuclear medicine at Tri-City Medical Center in Oceanside for over 18 years. His areas of expertise and special interest include PET imaging for cancer and Alzheimer’s Disease, ProstaScint imaging, new techniques of image fusion with MRI and CT, nuclear cardiology and infection imaging.
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