ProstaScint Scan: Contemporary Use in Clinical Practice

ADVANCES IN PROSTATE CANCER ProstaScint® Scan: Contemporary Use in Clinical Practice Samir S. Taneja, MD Department of Urology, New York University School of Medicine, New York University Cancer Institute, New York, NY Indium In 111 capromab pendetide (ProstaScint®; Cytogen Corporation, Princeton, NJ), a radiolabeled monoclonal antibody to prostate-specific membrane antigen, offers a potential means of localizing sites of soft tissue metastasis in prostate cancer patients. Although the test was previously limited by poor positive predictive value and specificity owing to the inherent limitations of single photon emission computed tomography, improvements in techniques of anatomic localization, along with increased reader experience, have significantly improved its accuracy. In addition to the conventional roles for ProstaScint, such as staging and detection of relapse, a number of new potential applications have emerged. [Rev Urol. 2004;6(suppl 10):S19–S28] ©2004 MedReviews, LLC Key words: Prostate cancer • Imaging • Staging • ProstaScint® ecause the contemporary diagnosis of prostate cancer is largely based on the measurement of serum prostate-specific antigen (PSA) levels, the disease has been identified at progressively earlier points in its natural history. Early diagnosis, at small volumes of cancer, brings about inherent difficulties in staging and identification of relapse. To this end, recent attempts to refine imaging have focused on molecular techniques that take advantage of the biologic characteristics of prostate cancer. B VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY S19 Contemporary Uses for ProstaScint continued Indium In 111 capromab pendetide (ProstaScint®; Cytogen Corporation, Princeton, NJ), a radiolabeled monoclonal antibody to prostate-specific membrane antigen (PSMA), offers a potential means of localizing sites of soft tissue metastasis. The test is approved by the US Food and Drug Administration for the imaging of prostate cancer patients. Patients receive an intravenous infusion of 5.0 mCi of radiolabeled antibody, followed by planar and crosssectional single photon emission computed tomography (SPECT). Repeat images are obtained 4 to 5 days later to allow wash-out of the isotope from the blood vessels and bowel. Simultaneous technetium-99m–labelled red blood cell (RBC) scanning allows assessment of the RBC pool to provide anatomic alignment of the blood vessels and to identify blood pool asymmetry within the ProstaScint image (Figure 1). Although the conceptual design and performance of the ProstaScint product is appealing, it historically suffered from a relatively poor specificity and tremendous operator dependence at low volumes of prostate cancer owing to the inherent limitations of SPECT imaging. Recent advances in image overlay, along with increasing experience in interpreting the scan, have created a renewed interest in integrating ProstaScint into the clinical management of prostate cancer. In this article, we reevaluate the clinical role of ProstaScint scanning in contemporary practice. Basic Biology PSMA is a membrane-bound epitope selectively expressed in epithelial cells of prostatic origin. It was originally identified by Horoszewicz and colleagues upon the creation of monoclonal antibodies to the cell membrane of prostate cancer cell line LNCaP.1,2 The antibody created, 7E11C5.3, recognizes PSMA. Ultimate characterization of the protein revealed that it is expressed in all prostate cells, including normal and A B Figure 1. Indium In 111 capromab pendetide (ProstaScint), a radiolabeled monoclonal antibody to prostate-specific membrane antigen, allows anatomic localization of soft tissue metastases in prostate cancer patients. At 4 to 5 days after infusion of ProstaScint, image acquisition allows detection of sites of abnormal uptake within the abdomen and pelvis. Simultaneous infusion of technetium-99m–labelled red blood cells allows assessment of blood pool (A) for spatial alignment of the ProstaScint scan (B). Image provided by University Hospitals of Cleveland, Cleveland, OH. hyperplastic epithelium, prostatic-intraepithelial neoplasia, and prostate cancer.3–5 Its expression seems to be increased in prostate cancer relative to normal epithelium. An alternatively spliced variant confined to the cytosol, termed PSM, is present in larger quantities in benign epithelium.5 Interestingly, small amounts of PSMA expression have been noted in a variety of other organs as well as in endothelial cells in a number of tumors.6 The ProstaScint scan was developed through radiolabeling of the 7E11C5.3 antibody with indium-111. The radioactive label allows the detection of be less relevant for radionuclide-based imaging and therapeutic applications that do not require such selectivity. Studies of cultured cells subsequently demonstrated uptake of the antibody by viable LNCaP cells.7 Two hours after antibody exposure, labeling intensity was similar to that of nonviable, fixed cells. Thus, it seems that despite the intracellular location of the antibody’s epitope, ProstaScint is able to detect viable foci of prostate cancer. Pathologic correlation of ProstaScint findings suggests that the scan is capable of detecting soft tissue metastases in humans with good accuracy.8–10 In a re- Despite the intracellular location of the antibody’s epitope, ProstaScint is able to detect viable foci of prostate cancer. prostate cancer cells in both prostatic and extraprostatic sites. Because the 7E11C5.3 antibody recognizes the intracellular portion of the membranebound component, there was initial skepticism regarding the ability of the scan to detect viable prostate cancer cells, although such a distinction might S20 VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY cent study of 31 patients who underwent lymph node sampling after an abnormal ProstaScint scan, an overall scan accuracy of 68% was seen.8 When evaluated by surgical site, the sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) of the scan were 94%, 42%, 53%, Contemporary Uses for ProstaScint and 92%, respectively. When analyzed by individual patient, the same data for the scan were 100%, 33%, 62%, and 100%, respectively.8 lack of effective treatment alternatives to conventional surgery and radiation, most clinicians were reluctant to withhold therapy on the basis of equivocal or poorly interpreted prostate cancer patients with at least 2 years of follow-up after having been scanned. Patients with a positive scan were 2.8 times more likely to have died during the median 4-year Desired Role in Clinical Practice Given the biologic mechanism of ProstaScint in identifying the prostate cancer cells in intraprostatic and extraprostatic sites, the desired applications of the test at its inception were intuitive. In patients newly diagnosed with prostate cancer, the test has provided a potential means of improving staging accuracy in the determination of extraprostatic disease. In individuals presenting with clinically localized disease, tests such as CT and MRI rarely demonstrate soft tissue metastases. Use of a biologic test potentially overcomes the poor resolution of anatomic tests in patients with low-volume disease. The impact of such a test is also clear for those individuals at high risk of extraprostatic disease and primary treatment failure. In patients with obvious nodal metastases, surgery and possibly local radiotherapy might be avoided in favor of systemic therapy. For those individuals with rising serum PSA levels after primary therapy, the ProstaScint scan has offered the potential to characterize the nature of recurrence. Distinguishing between clinically localized and metastatic recurrence, in the prostate or prostate bed, is of relevance to practicing urologists when determining whether local salvage therapy for potential cure is appropriate. For such patients, early detection of extraprostatic disease is fundamental because local treatments are most effective at minimal amounts of disease and lower absolute PSA values. Owing to the inherent limitations of SPECT imaging, problems of low specificity and interpreter inexperience limited the initial application of ProstaScint. Additionally, given the In the hands of experienced readers, the ProstaScint scan offers a valuable tool for the staging of prostate cancer. scan findings. Increasing experience in ProstaScint interpretation, along with various technological advances, has made the test a more reliable parameter in many centers. In addition, the increasing interest in multimodal approaches in the treatment of highrisk disease offers new potential applications for the ProstaScint scan in selecting patients for emerging treatment strategies. Role in Staging of Prostate Cancer The staging ability of the ProstaScint scan has been evaluated by a number of investigators. The highly variable reports of staging accuracy are clearly a function of 1) the experience of the interpreter, 2) the prevalence of extraprostatic disease in the study population, 3) the extent of lymph node sampling at the time of pathologic correlation, and 4) the inherent limitations of SPECT imaging. To date, no staging study has followed up on ProstaScint-positive patients to determine whether they have a higher risk of relapse. As such, although pathologic correlative studies might show discordance between nodal staging and scan findings, the clinical significance of a positive ProstaScint scan is, as yet, not entirely defined. However, Haseman and colleagues11 presented results from a retrospective outcomes study that was designed to determine the prognostic significance of ProstaScint scan. The study included a review of the records of 341 follow-up period than those without such a finding. The authors concluded that “the pattern of multifocal capromab pendetide uptake in the central abdominal region indicates a poor prognosis.”11 The ability to interpret the scan is critical. Because the findings of the study are often subtle, with a high risk of false-positive results due to bowel or blood vessels overlying the lymph nodes, there might be an improvement in interpretive accuracy as the reader becomes more experienced. In the hands of experienced readers, the scan does seem to offer a valuable tool for the staging of prostate cancer (Figure 2). The PPV of the scan varies in published reports from 11% to 66.7% in patients selected for radical prostatectomy.12–15 In some series of high-risk patients, the PPV was improved, likely in part because of the increased prevalence of metastatic nodal disease. Clearly, among low-risk patients, the PPV and specificity of the test are decreased. In most studies to date, the predictive ability of ProstaScint is superior to that of CT/MRI in detecting lymph node metastases before therapy. In one study of 160 men with highrisk disease defined by Gleason score, PSA, and clinical stage, 152 were studied with ProstaScint before surgical staging.13 Of 64 patients with positive lymph nodes, 40 were read as positive by ProstaScint scan (PPV  62%). Of 88 patients without lymph node metastases, 63 were read as neg- VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY S21 Contemporary Uses for ProstaScint continued Figure 2. A pretreatment overlay study demonstrated evidence of disease within the left seminal vesicle (single arrow) as well as left prostate base and midzone (double arrow). Image provided by Avon Medical Center, Avon, OH. ative by ProstaScint (specificity  72%). Overall, the sensitivity for detection of lymph node metastases was 62%. In this study, CT and MRI demonstrated PPVs of only 4% and 15%, respectively. In a second study evaluating highrisk disease, 22 men deemed high risk on the basis of pretreatment PSA level (mean 16 ng/mL) or disease volume underwent preoperative ProstaScint scans.14 At the time of surgery, obturator and common iliac node dissections were performed for pathologic correla- tion. A total of 88 data points, referring to each of the 4 nodal packets in each patient, were defined and correlated. cal follow-up of this cohort is warranted to determine whether patients with positive ProstaScint scan results For those individuals with rising serum PSA levels after primary therapy, the ProstaScint scan has offered the potential to characterize the nature of recurrence. Although the PPV was low (11%), the NPV was high (94%), suggesting that the test carried some clinical value in this high-risk population. Clearly, clini- S22 VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY are at higher risk of biochemical relapse. Given the poor sensitivity and predictive value of CT/MRI in predicting Contemporary Uses for ProstaScint extraprostatic disease, many clinicians rely on algorithms or nomograms to predict the risk of lymph node metastases. Polascik and colleagues16 compared the ability of several clinical algorithms and ProstaScint scans to predict lymphatic metastases in 198 men with clinical T2 to T3 disease undergoing radical prostatectomy. A total of 39% of patients in this high-risk cohort were found to have lymph node metastases at surgery. Among lymph node–positive patients, 40.5% to 45.4% were predicted by clinical algorithm, compared with 66.7% by ProstaScint alone. When integrating ProstaScint with clinical algorithms based on Gleason score, disease volume, and preoperative PSA level, a PPV of 72.1% could be achieved. As such, in evaluating patients before treatment, the use of ProstaScint scan might be particularly useful in staging individuals in the intermediate- to high-risk category Although limited by its risk for false-positive readings in inexperienced hands, the ProstaScint scan offers a useful tool for detection of lymph node metastases in newly diag- nosed prostate cancer. Through its relatively high NPV, its use in high-risk disease allows the appropriate selection of candidates for potentially curative therapies. The high rate of falsepositive results precludes its use in low-risk patients, but in those individuals with a high prevalence of nodal metastases, its use might allow selection into multimodal therapeutic strategies designed to improve treatment outcomes. Current efforts to improve specificity (described below) include fusion of the SPECT-acquired images with three-dimensionally reconstructed MRI.17 Role in Detection of Recurrent Disease One potentially useful application of ProstaScint scanning in prostate cancer patients is in the characterization of biochemical relapse. Biochemical relapse after local therapy refers to the clinical scenario in which patients treated with either surgery or local radiation are found to have a rising PSA level with no evidence of measurable or evaluable disease on conventional radiologic imaging, such as CT, MRI, Figure 3. ProstaScint/CT overlay of a patient with a rising prostate-specific antigen (PSA) level after brachytherapy 7 years earlier. His current PSA level was 1.8 ng/mL. The ProstaScint/CT overlay demonstrates strong uptake within a small lymph node in the interaortocaval groove (arrow). Image provided by University Hospitals of Cleveland, Cleveland, OH. or bone scan. At the time of biochemical relapse, the rise of PSA is generally due to local recurrence in the prostate or prostate fossa, metastatic recurrence, or a combination of both local and metastatic recurrence. Because those with isolated local recurrence might still be candidates for local curative treatments (salvage radiotherapy for surgically treated patients, salvage surgery or cryoablation for radiated patients), it is highly desirable to use molecular imaging techniques to discern the nature and location of relapse (Figure 3). Numerous definitions exist for relapse after primary therapy, but within the context of this discussion, the critical element remains defining the nature of the relapse. Investigators have proposed a number of strategies to define metastatic disease at the time of relapse, but the majority has concluded that a combination of prognostic variables and clinical parameters, including PSA velocity, is the most useful means of predicting isolated local recurrence. Relapse After Radical Prostatectomy In the case of men with biochemical relapse after radical prostatectomy, the attention of the clinician is generally focused on determining whether patients should be considered for salvage radiotherapy, early hormonal ablation, or observation. The natural history of biochemical relapse in this cohort is poorly defined, but it is believed that only 30% to 40% of such men will develop clinical evidence of metastatic disease by 10 years of follow-up.18 Nonetheless, overall low rates of response to salvage radiotherapy suggest that the majority of individuals with relapse might have metastatic disease at presentation. Given the low overall incidence of isolated fossa recurrence after prostatectomy, risk stratification is essential in identifying candidates for salvage VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY S23 Contemporary Uses for ProstaScint continued radiotherapy. Clinical parameters, such as interval to recurrence, pretreatment PSA level, and presalvage PSA level, have been implicated as predictors of the presence of metastatic disease. Those individuals with disease recurrence within 1 year of prostatectomy or pretreatment PSA levels higher than 10 ng/mL are most likely to have metastatic disease, whereas men with presalvage PSA levels higher than 1.0 ng/mL are not likely to respond durably to salvage radiotherapy. Similarly, several pathologic variables have been implicated in the prediction of metastatic disease at the time of biochemical relapse. A Gleason score of 8 or more, seminal vesical invasion, and extracapsular extension are all considered predictors of a higher likelihood of metastatic disease at the time of relapse. In one study of patients undergoing salvage radiotherapy, no patient with a Gleason score of 8 or more, relapse within 1 year of surgery, or seminal vesicle invasion maintained a durable response to radiotherapy.19 The rate of PSA rise, measured either as PSA velocity or PSA doubling time (PSA-DT), seems to be the strongest predictor of the likelihood of isolated fossa recurrence after radical prostatectomy. Several investigators have demonstrated that a more rapid PSA-DT correlates with a higher likelihood of metastatic relapse.20–23 Most recently, PSA-DT at the time of biochemical recurrence after surgery or radiation was shown to be a surrogate marker of subsequent metastatic disease and disease-related mortality.24 Fossa biopsy to identify local recurrence does not address the fundamental question of whether extraprostatic or metastatic disease is present. And, although the presence of fossa recurrence on biopsy does not rule out metastatic relapse, the absence of fossa recurrence on biopsy also does not rule out isolated recurrence. In general, those patients likely to respond favorably to salvage radiotherapy are not likely to have sufficient disease to reliably detect recurrence on biopsy. Typically, local recurrence is not identified by local imaging until adequate disease volume for detection exists. In the case of biochemical relapse after radical prostatectomy, this is not usually the case at PSA levels below 1.0 ng/mL. Conventional imaging studies (eg, MRI and CT) rarely demonstrate measurable disease upon relapse in the setting of low (1.0 ng/mL) serum PSA levels, and as such, molecular imaging studies such as ProstaScint might offer the greatest ability to detect extraprostatic recurrence.25–27 As in the case of staging before therapy, extraprostatic disease detec- prostatectomy (PSA range 0.1–4.0 ng/mL), 72% demonstrated abnormal uptake on ProstaScint; 31% of patients were determined to have isolated fossa recurrence.31 Interestingly, the investigators observed no minimum PSA value at which isolated fossa uptake could be seen. Unfortunately, the investigators reported no outcomes of salvage therapy, and as such, the significance of isolated recurrence or negative scan was not discernible from this study. In the absence of pathologic correlation, the best means of assessing the accuracy of ProstaScint in evaluating local recurrence is in comparing the findings of the scan with the outcome of salvage radiation. Kahn and colleagues32 reported that 80% of men with a negative ProstaScint scan at the time of recurrence had a favorable Men with ProstaScint uptake limited to the prostatic fossa displayed a 62% likelihood of favorable response, compared with only 27% of men with evidence of extraprostatic disease on presalvage scan. tion is, in part, a function of the experience of the reader. Elgamal and colleagues28 reported on the follow-up of 100 patients with recurrence after primary therapy and a mean PSA level of 55.9 ng/mL. In 42.9% of patients, an isolated local recurrence was seen, whereas in 49% of patients, lymph node metastases were identified. When tested against the pathologic outcome of lymph node sampling, the test displayed 89% sensitivity and 67% specificity. In a similar evaluation of men at recurrence, ProstaScint identified extraprostatic recurrence in 42% of men evaluated.29 In a larger cohort of men followed for primary or recurrent disease, ProstaScint outcomes correlated significantly (P  .033) with the likelihood of isolated fossa recurrence.30 In a series of 255 patients with biochemical recurrence after radical S24 VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY response to salvage radiotherapy. Similarly, men with ProstaScint uptake limited to the prostatic fossa displayed a 62% likelihood of favorable response, compared with only 27% of men with evidence of extraprostatic disease on presalvage scan. Wilkinson and Chodak33 evaluated 42 men with biochemical relapse and proceeded with salvage radiotherapy in 15 with evidence of isolated local recurrence. The initial and durable responses to radiation among these individuals were 66.7% and 46.7%, respectively. In a separate study by Thomas and colleagues,34 patients with ProstaScint uptake outside the prostatic fossa were at an increased likelihood of durable response to radiotherapy compared with those with negative scan or uptake limited to the prostatic fossa. This study has been criticized for the use of Contemporary Uses for ProstaScint older image-acquisition technologies, which draws into question the accuracy of the imaging techniques. Presalvage PSA levels in this cohort ranged as high as 5.7 ng/mL, illustrating that ProstaScint findings likely cannot be interpreted independent of other factors predictive of response to salvage radiotherapy. Clearly, in predicting the likelihood of durable response to salvage radiotherapy for the individual patient, the clinician must incorporate other variables. The likelihood of ProstaScint scan to identify extraprostatic disease will increase with increasing presalvage PSA level, as will the specificity of the positive scan. Conversely, the likelihood of durable response will decrease with increasing PSA level at the time of salvage. Relapse After Radiotherapy Contemporary salvage techniques for individuals with rising serum PSA levels after radiotherapy include surgical excision of the prostate and cryosurgical ablation of the residual gland. As such, not unlike the scenario of biochemical relapse after surgery, it is of critical importance to identify those men with recurrence isolated to the prostate to properly select candidates for salvage therapy. The general principles of evaluation are similar to those of the patient demonstrating relapse after radical prostatectomy. In the case of radiation failure, it is critical to confirm the presence of residual disease in the prostate before initiating invasive salvage therapy. Biopsy of the gland is therefore necessary to confirm residual disease. One must recognize, once again, that the presence of residual disease in the gland does not rule out the possibility of metastatic disease in other sites. ProstaScint can be useful in identifying uptake in the residual prostate. Although confirmatory biopsy is necessary, strong uptake in the residual prostate should be pursued aggressively, even in the absence of a positive initial biopsy. Currently used overlay techniques (described below) can help to localize uptake to a region of the prostate, thereby allowing the biopsy to be focally directed. Ultimately, decisions regarding salvage therapy in the patient with biochemical relapse after radiotherapy must be made within the context of multiple factors. Just as in the case of surgery, pretreatment variables, such as Gleason score, PSA level, and clinical stage, must be considered along with posttreatment PSA nadir, time to relapse, and PSA velocity upon relapse. In the case of radiotherapy, higher-risk patients are generally selected for therapy, and therefore, those relapsing might be less likely overall to experience isolated recurrences in the prostate. If patients are at high risk for metastatic disease before therapy, they will remain so after relapse. Image Overlay to Improve Specificity Because anatomic localization of ProstaScint uptake has been a histori- cal problem limiting specificity, many investigators have reported on the fusion of ProstaScint images with crosssectional images of CT or MRI. Such image overlay theoretically allows the reader to discern false-positive uptake in bowel or blood vessels overlying lymph nodes (Figure 4). In addition, lymphadenopathy noted on crosssectional imaging, particularly those that are equivocal in size, can be confirmed as abnormal by overlay images. Finally, the use of pelvic overlay can localize ProstaScint to the prostate or seminal vesicles (Figure 5). The use of a fused ProstaScint and MR/CT image has resulted in improved outcomes in our institution. In an evaluation of 67 men with rising PSA after primary therapy, 58 were evaluable for comparison of ProstaScint and fusion study results.17 Of 161 positive prefusion extraprostatic sites, 74 were found to be negative after image fusion. An additional 13 sites, not identified on ProstaScint alone, were identified through the fusion study. This resulted in conversion of 25 patients from a reading of extraprostatic disease to a reading of Figure 4. Image fusion of ProstaScint and CT demonstrates clear localization of uptake to an enlarged lymph node and not the adjacent blood vessels (arrow). Image provided by University Hospitals of Cleveland, Cleveland, OH. VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY S25 Contemporary Uses for ProstaScint continued Role in Prediction of Prognosis or Disease-Related Risk Figure 5. As a potential application of ProstaScint image fusion, overlay of the ProstaScint on CT or MRI of the pelvis can provide confirmation of occult disease within the prostate in individuals 1) relapsing after radiotherapy, 2) with a high prostate-specific antigen level despite negative biopsy, and 3) requiring correlation of endorectal MRI findings. In this study, ProstaScint (upper panels) is fused with CT (middle panels) to provide anatomic localization of the signal to the left prostate midzone (arrow). Image provided by Avon Medical Center, Avon, OH. isolated local recurrence. In follow-up, determination of the efficacy of salvage radiotherapy in these patients will allow a determination of the impact of image fusion in the evaluation of recurrent disease. In a previous unpublished preliminary study,35 we found that the specificity of ProstaScint in predicting response to salvage radiotherapy was increased to 69% upon integration of image fusion. Role in Diagnosis of Prostate Cancer For select patients, ProstaScint might offer potential help in the diagnosis of prostate cancer. In those men who have a persistently elevated or rising PSA level but negative prostate biopsy, few diagnostic tests are available for the identification of occult malignancy. In those patients who are diagnosed with cancer on repeat biopsy, pathologic fol- low-up has most often demonstrated the cancer to be present in the transition zone or anterior prostate. Endorectal MRI with spectroscopic evaluation of the prostate tissue can be useful in identifying the location of cancer in such patients, but it suffers from a poor resolution of cancer foci located in the transition zone.36 Although primary disease detection was not studied in the original clinical trials, the ability to overlay ProstaScint on cross-sectional imaging provides a new potential role for ProstaScint in identifying increased uptake in the gland itself (Figure 5). In this case, equivocal findings on MRI or MR spectroscopy could be overlaid with ProstaScint to grade the clinician’s degree of suspicion in deciding when and where to perform a repeat biopsy. This role for ProstaScint remains to be validated. S26 VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY As previously mentioned, PSMA expression has been noted to be increased in cancer relative to benign epithelium in the prostate. Likewise, the expression has been noted to be greater in metastatic tissues relative to localized prostate cancer. In a recent study, immunohistochemical staining of 136 primary prostate cancer specimens was carried out to determine the relationship of PSMA expression to adverse pathologic characteristics and the likelihood of relapse.37 Strong PSMA staining correlated with tumor grade (P  .030), pathologic stage (P  .029), aneuploidy (P  .010), and biochemical recurrence (P  .001). In multivariate analysis of conventional risk factors, only pathologic stage (P  .018) and PSMA staining (P  .002) were independent predictors of biochemical recurrence. The significance of this finding remains to be defined in clinical practice. If in fact PSMA expression accurately predicts a subset of prostate cancer patients in whom disease progression is more likely, then it, like PSA-DT, could serve as a surrogate marker to identify patients who might be better candidates for 1) immediate adjuvant therapy, 2) multimodal therapy, or 3) early hormonal intervention. Obviously, before initiating changes in practice standards, these findings need to be validated by prospective and/or largerscale studies. Recommendations for Use Historically, the clinical application of ProstaScint has been limited owing to highly variable reader interpretation, poor specificity among patients with low-volume disease, and inherent limitations of SPECT imaging. Because the majority of patients who would benefit from ProstaScint are those individuals with small-volume disease not detected by conventional imaging, Contemporary Uses for ProstaScint it has often been difficult to integrate the test into clinical practice in a meaningful way. The combination of improved technology and increased reader experience in interpreting ProstaScint has resulted in a need for reevaluation of the test. The use of image overlay or fusion has potentially changed the impact of ProstaScint scanning through a reduction in false-positive results. As such, clinical applications in which clinical management. As such, lowrisk patients with small-volume, early-stage cancer will not likely benefit from the use of ProstaScint before local therapy. Intermediate- to high-risk patients can be considered for ProstaScint if 1) multimodal treatments are being considered, 2) other staging tests suggest extraprostatic disease and validation is required, or 3) clinical parameters such as PSA level, Gleason score, or digital exami- The ideal patients to benefit from ProstaScint scan in the setting of biochemical relapse might be those with high-risk features, such as a high presalvage PSA level or Gleason score. ProstaScint has traditionally been perceived to be insufficient should be revisited to determine whether the test will now provide sufficient accuracy to aid in clinical management. With the emergence of multimodal approaches to prostate cancer treatment, the identification of extraprostatic disease sites in those individuals at high risk before conventional therapy is highly desirable. Such an observation must have considerable accuracy if it is to allow alteration of nation suggest a high likelihood of advanced disease despite negative conventional imaging. Despite improved ability to anatomically localize ProstaScint uptake, the potential for false-positive results still exists. If conventional therapy is to be withheld on the basis of ProstaScint findings, this must be within the context of other parameters, as outlined above. ProstaScint might offer valuable information in the management of individuals with biochemical relapse after local therapy. In this setting, ProstaScint alone does not seem to offer sufficient accuracy to supersede other predictive factors, such as PSA level, Gleason score, pathologic stage, and PSA-DT. Additionally, the accuracy of the test is likely decreased in patients with smaller volumes of disease. Given the experience of several investigators demonstrating increased responses to salvage radiotherapy among patients with negative ProstaScint scan results or isolated local uptake, there seems to be a clear role for ProstaScint in this clinical setting. An evaluation of the relationship of ProstaScint to other predictive parameters is necessary to properly define indication and interpretation. As such, the ideal patients to benefit from ProstaScint scan in the setting of biochemical relapse might be those with high-risk features, such as a high presalvage PSA level or Gleason score. In this setting, the scan might identify a subset of patients likely to respond favorably to salvage therapy despite other adverse prognostic variables, such as the PSA level, Gleason score, and PSA velocity. In the low-risk patient (defined by slow PSA velocity, Main Points • Recent advances in image overlay, along with increasing experience in interpreting the scan, have created a renewed interest in integrating ProstaScint® (Cytogen Corporation, Princeton, NJ) into the clinical management of prostate cancer. • In the hands of experienced readers, the ProstaScint scan can be a valuable tool for the staging of prostate cancer; in most studies to date, the predictive ability of ProstaScint was superior to that of CT and MRI in detecting lymph node metastases before therapy. • Conventional imaging studies (eg, MRI and CT) rarely demonstrate measurable disease upon relapse in the setting of low (1.0 ng/mL) serum prostate-specific antigen levels, and as such, molecular imaging studies such as ProstaScint might offer the greatest ability to detect extraprostatic recurrence. • After radiotherapy, it is of critical importance to identify those men with recurrence isolated to the prostate to properly select candidates for salvage therapy; ProstaScint can be useful in identifying uptake in the residual prostate. • The fusion of ProstaScint images with cross-sectional images of CT or MRI can increase the specificity of results; such image overlay theoretically allows the reader to discern false-positive uptake in bowel or blood vessels overlying lymph nodes. • Intermediate- to high-risk patients can be considered for ProstaScint if 1) multimodal treatments are being considered, 2) other staging tests suggest extraprostatic disease and validation is required, or 3) clinical parameters suggest a high likelihood of advanced disease despite negative conventional imaging. VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY S27 Contemporary Uses for ProstaScint continued low PSA level, and favorable disease pathology), the ProstaScint can be confirmatory in predicting favorable response to salvage radiotherapy, but the presence of extraprostatic uptake on the scan will carry lower specificity. As such, ProstaScint scan should not be the sole variable to exclude low-risk patients from salvage treatment. Newer applications of ProstaScint, such as detection of locally recurrent disease after radiation, detection of undiagnosed prostate cancer, or assessment of the biologic aggressiveness of malignancy, remain to be validated. Nonetheless, the test exists as a means of identifying or confirming the presence of occult disease in the prostate both in the setting of relapse and in patients for whom standard biopsy techniques are nondiagnostic.  References 1. 2. 3. 4. 5. 6. 7. 8. 9. van Steenbrugge GJ, Groen M, van Dongen JW, et al. 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