ProstaScint imaging in nuclear medicine

PROSTASCINT IMAGING in DETECTION of BONE METASTASES in PROSTRATE CANCER: EXAMINATION of FALSE POSITIVE and FALSE NEGATIVE RESULTS and the ACCURACIES & INACCURACIES in DETECTION & DIAGNOSIS

The objective of this work is to make an extensive review of literature in the area of ProstaScint imaging effectiveness and accuracy in detecting distant metastases, and specifically bone metastases. This study specifically seeks findings concerning false positive and false negative results and the inaccuracies or accuracies in diagnosis of metastatic bone lesions due to prostrate cancer.

As the knowledge and experience in the clinical use of ProstaScint Imaging in detection of bone metastases in prostrate cancer grows the capacity to use this imaging in detection of prostrate bone metastases grows as well as does the accuracy of the use of ProstaScint imagine in this area of cancer detection, diagnoses and treatment.

LITERATURE REVIEW

The work of Samir Taneja (2004) entitled: "Imaging in the Diagnosis and management of Prostrate Cancer" published in the Urology Review relates a study of 160 men with high-risk disease defined by Gleason score, PSA, and clinical stage, 152 were studied with ProstaScint prior to surgical staging. www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1472828" 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 negative by ProstaScint (specificity = 72%). Overall, the sensitivity for detection of lymph node metastases was 62%." Taneja states that in the reported study that CT and MRI "...demonstrated PPV of only 4% and 15%, respectively. Given the poor sensitivity and predictive value of CT/MRI in predicting extraprostatic disease, many clinicians rely upon algorithms or monograms to predict the risk of lymph node metastases." (Taneja, 2004) Taneja relates that Polascik and colleagues conducted a comparison of www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1472828" the ability of several clinical algorithms and ProstaScint scans in their prediction of lymphatic metastases. The participants in the study were 198 men with clinical T2-3 disease undergoing radical prostatectomy. The study states findings that "...of 39% of patients in this high-risk cohort were found to have lymph node metastases at surgery. From 40.5% to 45.4% of lymph node positive patients were predicted by clinical algorithm compared to 66.7% by ProstaScint alone. When integrating ProstaScint with clinical algorithms based upon Gleason score, disease volume, and pre-operative PSA, a PPV of 72.1% could be achieved." (Taneja, 2004) Included in the study's findings is that in the evaluation of patients "...prior to treatment, the use of ProstaScint scan may 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 diagnosed prostate cancer. Its use in high-risk disease allows the appropriate selection of candidates for potentially curative therapies. Current efforts to further improve specificity include fusion of the SPECT acquired images with 3D reconstructed MRI or CT." (Taneja, 2004) it is particularly important to note the statement of Taneja as follows: "The staging ability of the ProstaScint scan has been evaluated by a number of investigators. A fundamental necessity of the scan is experience in the interpreter. As the findings of the study are often subtle, with a high risk of false positive due to bowel or blood vessels overlying the lymph nodes, there may be an improvement in interpretive accuracy as the reader becomes more experienced. In the hands of experienced readers, the scan does appear to offer a valuable tool for staging of prostate cancer. The importance of reader experience in interpretation of ProstaScint scans is made evident by the reported data regarding staging. The PPV of the study varies in published reports from 11% to 66.7% in patients selected for radical prostatectomy (RP). In those series evaluating high-risk patients, the PPV was improved, probably due, in part, to the increased prevalence of metastatic nodal disease. In most studies to date, the predictive ability of ProstaScint is superior to that of CT/MRI in detecting lymph node metastases prior to therapy." (2004) Taneja (2004) claims that ProtaScint is capable of identifying the pelvis and retroperitoneal region nodes and when tested "against the pathologic outcome of lymph node sampling, the test displayed 89% sensitivity and 76% specificity." (Tenaja, 2004) ProstaScint is stated of Tenaja (2004) to have identified 42% of extraprostatic recurrence of patients evaluated. The study of Kahn (2007) reports 42% extraprostatic recurrence in 42% of evaluated patients evaluated. In a separate and larger study, Sodee and Faulhaber (2000) followed a cohort of patients for primary or recurrent disease and relates that "ProstaScint outcomes correlated significantly with the likelihood of isolated fossa recurrence."

The work of Quintana and Blend (2000) entitled: "The Dual-Isotope ProstaScint Imaging Procedures: Clinical Experience and Staging Results in 145 Patients" published in the Journal of Clinical Nuclear Medicine reports a study evaluating the effectiveness of ProstaScint for staging 145 patients with prostrate cancer, 19 newly diagnosed and 126 with recurrence. Results of the study that: "With clinical follow-up in 13 of 19 (68%) patients with primary disease, 10 of 13 (78%) had organ-confined disease. With follow-up in 64 of 126 (51%) patients with possible recurrent disease, 49 of 64 (77%) were found to have prostatic fossa activity only. Disease stage was deemed more advanced in 3 of 13 (22%) patients with primary cancer and in 13 of 64 (20%) of those with recurrent disease based on ProstaScint findings when all other imaging tests were inconclusive. Six patients with recurrent disease had negative results of their scans. In the 16 patients with more advanced disease, 3 of 59 lesions (5%) were documented as false positive, and there were no reported cases of false-negative findings." (Quintana and Blend, 2000) in one of two open-label, multi-center, uncontrolled pivotal phase 3 trials, 160 patients with a tissue diagnosis of prostrate cancer and who were considered to be high risk for lymph node metastases underwent Prostascint staging. Of these 160, 152 had an interpretable scan and surgical staging with 40 scans being true positive, 25 being false positive, 63 true negative and 24 false negative. The following figure shows the results for immunoscintigraphy.

The report states that sixty-five patients, or 43% had positive Indium in 111 ProstaScint images for pelvic lymph node metastases. Of these 65 patients 25 patients (38%) did not have metastatic prostrate cancer at surgery. Eighty-seven patients (57%) had negative Indium in 111 ProstaScint imagines: Of these 24 patients (28%) did have metastatic prostrate cancer at surgery. The overall accuracy in 111 ProstaScint immunoscintigraphy was 68%. A second open label, multi-center, uncontrolled pivotal phase 3 trial involving 183 patients with a high clinical suspicion of residual or recurrent prostate cancer following radical prostatectomy underwent evaluation. Patients with a rising PSA, a negative bone scan and a negative or equivocal standard diagnostic techniques underwent ProstaScint immunoscintigraphy before biopsy of the prostatic fossa. Results shown that 158 patients had a scan that was interpretable and prostatic fossa biopsy. Of these 158, 29 scans were false positive, 70 were true negative and 30 were false negative. The following figure shows the results of this study.

The study states: "Fifty-eight patients (37%) had positive Indium in 111 ProstaScint images in the prostatic fossa: Of these 50% (29 patients) did not have recurrent prostate cancer on biopsy. One hundred patients (63%) had negative Indium in 111 ProstaScint images: Of these 30% (30 patients) had recurrent prostate cancer on biopsy. The overall accuracy of Indium in 111 ProstaScint® immunoscintigraphy, as measured against prostatic fossa biopsy, was 63% (99/158)." (Rieger, 2001; ProstaScint Kit, nd)

It is related that clinical trials have not studied specifically the ability of ProstaScint to image distant (extra-pelvic) metastases, and a limited number of patients with distant (primarily bone) metastases were enrolled. The study states that 13 of 16 patients, or 81% with CT evidence of distant soft tissue disease had positive extrafossa ProstaScint scans. Of the 61 patients, 35, or 57% with bone scan evidence of disease had positive Indium in the 111 ProstaScint skeletal uptake; however Indium in 111 ProstaScint imaging did not identify most sites of abnormal bone uptake on bone scan. The Indium in 111 ProstaScint scan did, however, demonstrate sites of bone marrow metastases that were not seen on bone scan in 2 of 43 patients in the phase 1 study. (Rieger, 2001; ProstaScint Kit, nd)

The work of Mark Scholz entitled: "Newly Diagnose Prostrate Cancer: Evaluating the Options" states that in a multi-center study that compared ProstaScint imaging to PLND in 51 prostrate carcinoma patients who were identified as high risk for lymph node metastases, "ProstaScint surpassed the combined diagnostic performance of CT, MRI and U.S. with an overall accuracy of 81%." (2004) Scholz additionally states that other 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 previous pelvic lymph node dissections that were pathologically negative, but ProstaScint scans that were abnormal. The investigators noted that because patients who have skip metastases and negative pelvic lymph nodes have been found to later develop distant metastases, ProstaScint imagine was instrumental in detecting metastatic disease and prompting further investigation." (2004)

The work of Murphy and Troychak (2000) entitled: "Follow-Up Prostascint Scans Verify Detection of Occult Soft-Tissue Recurrence After Failure of Primary Prostate Cancer Therapy" published in the Prostrate Journal reports a study conducted for the evaluation of the ability of ProstaScint scan in the detection of prostatic bed recurrent and metastases to regional or distant lymph nodes. The study reported is of one hundred sequential patients who were evaluated with repeated ProstaScint scans due to evidence of recurrence during the disease course. These patients were followed from November 1994 and April 1999 and had "concurrent bone scans and serum prostate-specific antigen (PSA) evaluations. They have had hormone therapy (n = 53) and/or experienced a rising PSA after radical prostatectomy (n = 38) or after radiation therapy (n = 56). Scan images were scored 0-3, where score 0 = negative, score 1= prostate bed uptake, score 2 = regional lymph node uptake, and score 3 = distant lymph node uptake. In each patient, the uptake of the follow-up scan(s) was compared to that of the initial scan." (Murphy and Troychak, 2000)

Results of the study relate that the median age of participants was: "...70 years (range, 45-87), and 23 patients had a positive bone scan. The average PSA was 40.5 ng/ml (standard deviation, 223.5). There was 257 scans representing 100 patients. All patients had at least 2 scans, 35 patients had 3 scans, and 11 patients had 4 scans. No individual exhibited detectable adverse clinical reactions during or after the scan. The findings of the initial and consecutive scans were anatomically consistent in 79%, whereas in 21% there were skip metastases. In 24 patients the lesions progressed by scan and PSA, 10 patients showed progression of scan but no PSA progression, 49 patients showed no change, and 17 patients showed a remission related to adjuvant therapy." (Murphy and Troychak, 2000) Conclusions of this study state: "The consistency on repeating the scan (79%) and the high percentage of patients showing persistent uptake at the prostate bed (43%) as well as the percentage of detection of regional nodes (20%) and distant nodes (32%) reflects the importance of using the ProstaScint scan in finding occult recurrences after primary treatment failure of prostate cancer. These results are similar to those reported earlier in autopsy series studies in similar populations." (Murphy and Troychak, 2000)

The work of Murphy, Snow, Brandt and Brawer (2000) reports the evaluation of prostrate cancer patients who received multiple staging tests including ProstaScint scans and states that: "Multiple serum tests were performed on archival samples from patients who participated in trials to assess the ProstaScint scan staging ability. Traditional statistical analysis as well as artificial neural network (ANN) analysis were employed to evaluate individual patients and the group as a whole. The results were evaluated so that each factor was tested for prognostic value." (Murphy, Snow, Brandt and Brawer, 2000) Methods used in this study include data which was obtained from: "...serum tests, bone scans, and ProstaScint scans were evaluated by traditional statistical methods and ANN to determine the individual value in clinical staging of prostate cancer." (Murphy, Snow, Brandt and Brawer, 2000) Results of this study state: "Two hundred seventy-five patients (180 postprostatectomy, 95 intact prostate) with prostate cancer (14 with distant metastases) were available for analysis. Data available included: clinical state (remission or progression), most recent clinical TNM stage, bone scan, and ProstaScint scan. Serum was tested for prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), free PSA (fPSA), and complexed PSA (cPSA). Additional calculations included percent free PSA, and percent complexed PSA. Spearman individual statistical assessment for traditional group evaluation revealed no significant factors for T-stage. The free PSA and complex PSA had a significant association with node status. The distant metastases (M) stage correlated well with the bone scan and clinical stage. ANN analysis revealed no significant T-stage factors. N-stage factors showed a 95% sensitivity and 49% specificity. These factors included the presence or absence of a prostate, PSA serum levels, bone scan, and ProstaScint scans as major associated indicators. ANN analysis of the important variables for M-stage included ProstaScint scan score, and PSA levels (total, percent complexed, percent free, and fPSA). These factors were associated with a 95% sensitivity and 15% specificity level." (Murphy GP, Snow PB, Brandt J, Elgamal a, Brawer MK. (2000) Evaluation of prostate cancer patients receiving multiple staging tests, including ProstaScint scintiscans. Conclusions of the study state that: "Two hundred seventy-five patients receiving treatment for prostate cancer were evaluated by ANN and traditional statistical analysis for factors related to stage of disease. ANN revealed that PSA levels, determined by a variety of ways, ProstaScint scan, and bone scan, were significant variables that had prognostic value in determining the likelihood of nodal disease, or distant disease in prostate cancer patients." (Murphy, Snow, Brandt and Brawer, 2000)

The work of Elgamal, Troychak and Murphy (1998) entitled: "Prostascint Scan May Enhance Identification of Prostate Cancer Recurrences After Prostatectomy, Radiation, or Hormone Therapy: Analysis of 136 Scans of 100 Patients" published in the Prostate Journal relates that: "Primary extraprostatic spread or failure after prostate cancer treatment can occur locally in the prostatic fossa and/or metastasize to regional and/or distant lymphatics and/or in bone." (Elgamal, Troychak and Murphy, 1998) it is reported by Elgamal, Troychak and Murphy that an evaluation of the "...ability of the ProstaScint (Cytogen Corp., Princeton, NJ) scan to identify soft tissue recurrence of prostate cancer in patients who failed primary treatment, and we monitored their responses to a secondary treatment. ProstaScint was evaluated in a series of 136 consecutive scans associated with a complete set of relevant clinical and biochemical data. These scans represented 100 patients, imaged between November 1994-May 1998, who underwent a definitive prostate cancer treatment followed by evidence of recurrence. All patients had serum prostate-specific antigen (PSA), Western-blot serum prostate-specific membrane antigen (PSMA), and bone scans. Prostatic fossa and/or lymph node biopsies were available in 33 patients." (Elgamal, Troychak and Murphy, 1998)

Results of the study state: "Overall, no adverse reactions were related to any of the radioactive antibody infusions. The average age was 69 years (range, 48-89 years), serum PSA was 55.9 ng/ml (range, 0-2,185 ng/ml), and serum PSMA was 0.32 (relative intensity levels range, 0.04-0.55). The initial therapies given were radical prostatectomy (55 scans), prostate radiation (74 scans), and/or hormonal therapy (77 scans). Twelve patients exhibited a negative scan. Local recurrence alone was identified in 58 scans (42.6%). Lymph node metastases were identified in 66 scans (48.5%). Of these, 21 had regional metastases alone, and 45 had distant lymph node metastases. Ten scans showed skip lymph node metastases without regional failure. PSA significantly correlated with negative, pelvic, and extrapelvic scan findings (P < or = 0.02). PSMA correlated best with pelvic recurrence and extrapelvic metastases in prostatectomized patients. Thirty-four patients had repeated scans for monitoring treatment response. Of these patients, 19 (56%) showed progression on the second scan, consistent with persistent increase in PSA and PSMA levels in all but 2 patients. Another 11 patients showed no change, and 4 patients showed partial remission, suggesting a response to the salvage treatment. All 20 positive prostate biopsies and 4 of the 7 positive lymph node biopsies correlated with ProstaScint findings, whereas 4 of the 6 patients with a negative biopsy had negative scans (i.e., 89% sensitivity and 67% specificity). Bone metastases were identified in 42 bone scans; 45% of these showed no lymph node metastasis on ProstaScint. In another 24 patients (57%), bone metastases were detected on ProstaScint examinations." (Elgamal, Troychak and Murphy, 1998)