Imaging with prostate-speci c membrane antigen (PSMA) in prostate cancer

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1 Paper (2000) 3, 47±52 ß 2000 Macmillan Publishers Ltd All rights reserved 1365±7852/00 $ Imaging with prostate-speci c membrane antigen (PSMA) in prostate cancer MR Feneley 1 *, H Jan 2, M Granowska 2, SJ Mather 2, D Ellison 2, J Glass 4, M Coptcoat 3, RS Kirby 5, C Ogden 4, RTD Oliver 1, DF Badenoch 1, FI Chinegwundoh 1, VH Nargund 1, AMI Paris 1 & KE Britton 2 1 Departments of Urology, Royal Hospitals NHS Trust, London, UK; 2 ICRF Nuclear MedicineGroup,RoyalHospitalsNHSTrust,London,UK; 3 King's College Hospital, London, UK; 4 Northwick Park Hospital, London, UK; and 5 St George's Hospital, London, UK Radioimmunoscintigraphy using a radio-labelled antibody to prostate-speci c membrane antigen (PSMA) has growing applications as a means of tissuespeci c imaging based on functional characteristics and complements traditional staging investigations. Clinical applications in men with carcinoma of the prostate are being re ned, and this study reports outcomes with this technique in our practice. Prostatic immunoscintigraphy scans were performed with In-111 CYT 356 in 49 men with carcinoma of the prostate, obtaining sequential images in two and three dimensions at 10 min, 24 and 48 h. Of the 49 men, 36 had clinically localized cancer, 10 had recurrent disease after radical radiotherapy or radical prostatectomy and three had PSA after primary endocrine treatment. Scan ndings are discussed in the context of clinical management. Of the 36 men with clinically localized cancer, seven had increased uptake in regional and distant lymph nodes. Of these seven, three were treated with hormone manipulation, two by radical prostatectomy and two by radical radiotherapy. Among 10 patients who had recurrence after radical treatment of the primary tumour, scans showed local recurrence alone in four, and six had regional or distant metastases. Three patients treated with primary hormone manipulation had scans for PSA, and of these one had a positive regional node and two had distant soft tissue and bone metastases. In conclusion, prostatic radio-immunoscintigraphy scans highlight tissues involved by prostate cancer, including the prostate, lymph nodes, soft tissues and bone metastases as well as pelvic recurrence. Results may contribute to the clinical management of individual patients, although histological con rmation may be appropriate when considering alternative treatment. (2000) 3, 47±52. Keywords: prostate cancer; radio-immunoscintigraphy; prostate-speci c membrane antigen CYT 356 Introduction Adenocarcinoma of the prostate is the second most common cause of cancer death among men in most industrialised nations and, in England and Wales, it is *Correspondence: MR Feneley, James Buchanan Brady Urological Institute, Marburg Building, The Johns Hopkins Hospital, 600 N Wolfe Street, Baltimore, MD , USA. mfeneley@msn.com Received 23 November 1999; accepted 28 February 2000 responsible for around 9000 deaths every year. The development of locally advanced or metastatic disease is usually insidious and, for most patients presenting with symptoms, the tumour is all too frequently incurable and treatment essentially palliative. Early and radical treatment may be curative for localized tumours, particularly those that are organ-con ned, and may be recommended for men with life expectancy of at least 10 y. Appropriate therapeutic decisions are therefore dependent on accurate clinical assessment of tumour stage. Tumour stage as de ned by pathological examination has considerable prognostic importance in men treated by

2 48 radical prostatectomy for clinically localized disease. The risk of recurrence can be related to the presence of regional lymph node metastases, seminal vesicle invasion and involvement of surgical margins. Conventional radiological techniques including transrectal ultrasound (TRUS), computerized tomography (CT) and magnetic resonance imaging (MRI) have proved disappointing in the pre-operative assessment of local tumour invasion and diagnosis of soft-tissue and lymph node metastases. Growing experience with radio-immunoscintigraphy suggest that this technique may be useful for assessing tumour stage prior to treatment as well as monitoring disease progression and response after treatment. 1 It utilizes a radio-labelled antibody to a membrane-bound prostatic-speci c membrane antigen (PSMA) and this forms the basis for tissue-speci c imaging. This study examines the application of prostatic immunoscintigraphy in a variety of clinical situations, that include evaluation of clinically localized prostate cancer before radical treatment, recurrence after radical treatment, and assessment of disease progression. Methods We have scanned 49 patients with prostate cancer using In-111 CYT 356 (henceforth referred to as an immune scan for convenience). The study received Ethical Committee and ARSAC (Administration of Radioactive Substances Advisory Committee) approval, and each patient gave informed consent to participate. 100 ± 200 MBq In-111 labeled antibody was injected intravenously (24 msv/ 100 MB1). Scans were obtained using a Siemens Orbiter large eld of view (LFOV) camera and medium energy collimator. Planar two-dimensional images and singlephoton emission tomography (SPET) three-dimensional images were taken at 10 min, 24 and 48 h. Results Among the 49 patients who had immune scans, 36 were previously untreated and 13 were undergoing evaluation following treatment (Table 1 and 2). All 36 men who were previously untreated had clinically localized cancer and of these, seven had increased uptake consistent with metastatic cancer in regional and distant lymph nodes. Of these seven patients, three were subsequently treated with primary hormone manipulation, two had radical radiotherapy and two had radical prostatectomy with pelvic lymph node dissection. Sixteen patients had scans prior to radical prostatectomy: eight were retropubic operations with lymph node dissection, including two men with positive nodes on scans, and eight were perineal without histological lymph node evaluation. Three men with clinically localized prostate cancer and positive bone and/or immune scans were then treated with primary hormone manipulation: two had positive lymph nodes on scans and one had increased bone uptake on both immune and bone scans. Of the two patients with positive nodes on immune scan who later had radical prostatectomy, one had a scan positive obturator node and the other had a scan positive iliac node with scan negative obturator nodes. In both patients, no histological evidence of metastases was identi ed in the obturator nodes removed at lymph node dissection. However, both had non-organ-con ned disease with positive surgical margins. Nodal metastases were not identi ed in any of the six patients who had pelvic lymph node dissection and negative nodes on immune scan. Among the 13 patients scanned after treatment (Tables 1 and 2), 10 had recurrent disease after radical treatment of the primary tumour. Three of these had prior radical prostatectomy and three had received radiotherapy, and these individuals all had regional or distant metastases on immune scans and subsequently underwent hormonal treatment. Two patients had already received hormone manipulation for PSA recurrence after radical prostatectomy or radiotherapy, and in both cases the immune scan demonstrated local recurrence. One patient with a serum PSA level of 1.6 ng/ml after radical prostatectomy had local recurrence on immune scanning, but no evidence of regional or distant metastases, and after subsequent pelvic radiotherapy his PSA fell to an undetectable level ( < 0.1 ng/ml). One patient with detectable yet stable PSA at 0.4 ng/ml who also had evidence of local recurrence after radical prostatectomy was continued on observation. Three patients treated by primary endocrine manipulation were scanned after increasing PSA levels were Table 1 Patient pro le before and after radioimmunoscintigraphy Treatment after immunoscan Treatment before immunoscan Radical prostatectomy Radical radiotherapy Hormone manipulation Observation Untreated (new diagnosis) ạ Radical prostatectomy c 3. c 1 ḍ Radical radiotherapy c Primary hormone manipulation ḅ,c 2. c Radical prostatectomy subsequent hormone manipulation Radical radiotherapy 1 1. subsequent hormone manipulation Total a Includes two patients with lymphadenopathy on CT scanning and a third with bone scan positive for metastatic disease. b This patient had previous hormone manipulation for localized cancer. c These patients had serum PSA prior to scans. d This patient had a stable PSA prior to scan.

3 49 Table 2 Clinical evaluation of prostatic radioimmunoscintigraphy Prostatic immunoscintigraphy ndings Previous therapy Subsequent therapy n PSA Prostate Regional nodes Distant soft tissue metastases Bone metastases Bone scan ndings Untreated patients Untreated Radical prostatectomy ± 24.7 ng/ml Pos (16) Extracapsular (8) b solitary obturator node Untreated Radical radiotherapy ± 43 ng/ml Pos (17) Extracapsular (8) Untreated Hormone manipulation ± 25 ng/ml Extracapsular (3) solitary obturator node solitary iliac node solitary iliac and aortic nodes solitary iliac node solitary iliac node Neg Neg Pos (2) Pos (2): con rming immune scan Patients previously treated with radical prostatectomy or radical radiotherapy Radical prostatectomy only Watchful waiting ng/ml Local recurrence Neg Neg Neg Neg Radical prostatectomy only Radical radiotherapy to pelvis ng/ml a Radical prostatectomy only Hormone manipulation ± 5.0 ng/ml Radical radiotherapy only Hormone manipulation ± 419.0ml Patients on hormone therapy Hormone manipulation only Secondary hormone manipulation Hormone manipulation only Radical radiotherapy Hormone manipulation after radical prostatectomy Hormone manipulation after radical radiotherapy ± 62.0 ng/ml ng/ml Local recurrence Neg Neg Neg Neg Local recurrence (1) obturator and distant nodes Local recurrence (2) Extraprostatic (1) obturator and distant nodes Organ-con ned (2) obturator and distant nodes Local recurrence Ð extraprostatic isolated obturator node regional and iliac nodes isolated iliac nodes regional and iliac nodes aortic nodes hepatic and bone uptake regional, iliac and aortic nodes isolated hepatic and splenic Pos (1) con rming immune scan bone and distant metastases Neg uptake Neg Neg Neg No change 1 Local recurrence Neg Neg Neg No change ng/ml Local recurrence Ð extraprostatic Neg Neg Neg Pos a After radiotherapy, PSA level declined to undetectable level ( < 0.1 ng/ml). b Site of extracapsular extension did not correspond to the presence of cancer at prostatic or surgical margins. n ˆ number; PSA ˆ serum prostate speci c antigen; Pos ˆ positive (for cancer on scan); Neg ˆ negative (for cancer on scan). Scan ndings are given with number of pateints in brackets.

4 50 Figure 1 Prostate cancer: 24 h SPET images. (a) Transerve section: the prostate cancer is marked with a cross posterior to the bulb of the penis in red and between the two external iliac vessels in yellow. (b) Sagital section: uptake in the prostate cancer is shown with the cross posterior to the bulb of the penis in red and inferior to the smaller amount of activity in the bladder shown in yellow. Marrow uptake in the lower lumbar spine and sacrum is shown superiorly. Note: the prostate cancer is con ned to the prostate. There is no evidence of external spread or nodal involvement. measured on at least two occasions. One of these patients whose immune and bone scans showed no evidence of distant metastases later underwent radical radiotherapy to the pelvis with PSA normalization. The other two patients had metastatic progression and their immunscans showed distant lymph node, soft tissue and bony metastases: both of these patients went on to have further hormone manipulation. Illustrative examples of immune scans are given in Figures 1 ± 3. Figure 2 Prostate cancer: 24 h SPET images. The transverse section shows uptake extending posterior to the prostate (yellow cross). More extensive uptake is seen than in Figure 1 with some extension posteriorly through the capsule. Discussion This report describes the use of prostatic immunoscintigraphy in relation to clinical management for a variety of clinical situations. Several potentially useful applications are demonstrated, provided certain limitations in their interpretation are recognized. Firstly, the primary tumour can be speci cally imaged for men with clinically localized cancer. All 36 primary tumours were demonstrated unequivocally. Secondly, local recurrence after radical treatment of primary disease can be imaged. Among 10 patients, recurrence was con- ned to the prostatic bed after surgery in three, to the region of the prostate after radiotherapy in one, and six had recurrence in local or regional nodes (two with bone metastases also). Thirdly, the site and extent of metastatic progression can be assessed in men with hormone refractory disease.

5 Figure 3 Prostate cancer: 24 h SPET images. Transverse section: extensive uptake in the prostate cancer is seen in red with a posterior extension in yellow. To the right side posteriolaterally in yellow, uptake in an obturator node is visualized. The external iliac vessels are seen in red anteriorly. Prostate cancer extends posteriorly through the capsule with right obturator node involvement. Radical treatment of primary tumour may be offered to men with newly diagnosed, clinically localized cancer, and in these patients scans may identify sites of potential metastatic involvement that would have signi cant adverse prognostic implications but may not be manifest by a structural abnormality detectable by CT or MRI. In this series, 36 such men were scanned: eight proceeded to radical prostatectomy with pelvic lymph node dissection (including two with positive nodes on scans); eight had radical perineal prostatectomy without pathological staging of pelvic nodes (none of whom had scan positive nodes); 17 had pelvic radiotherapy (including two with scan positive nodes); and three had primary hormone manipulation (two of whom had scan positive nodes and one had corresponding positive bone and immune scans). It is generally well recognized that prognosis is signi cantly adversely affected by the presence of lymph node metastases, even when microscopic. 2 However, when this is not con rmed histologically the signi cance of scan positive nodes is uncertain. Antibody binding with regional nodes may re ect physiological processing of non-viable tumour cells, and even in the presence of metastases, the mechanism by which it binds the normally intracellular epitope is unclear. Previous studies suggest that serum PSMA levels and immune scans may provide prognostically signi cant information. 3 Histological examination and long-term outcome data are needed to evaluate the prognostic and therapeutic signi cance of soft tissue uptake in men with clinically localized cancer. After radical treatment of clinically localized cancer, prostatic immunoscintigraphy may be useful in men with PSA and negative bone scan. Our series included one patient whose immune scan appeared to demonstrate a potentially curable local recurrence in the prostatic fossa associated with a serum PSA after radical prostatectomy. Following radiation therapy to this site, serum PSA decreased from 1.6 ng/ml to an undetectable level ( < 0.1 ng/ml). Previous studies have suggested that among patients with recurrent cancer after radical prostatectomy, those with immune scans demonstrating disease con ned to the pelvis fare better than those with activity beyond the eld of radiation. 4 The potential bene t of irradiating local recurrent disease should be tempered by the risk of failing to control disease progression due to established distant micrometastases and the additional morbidity of pelvic radiation after radical surgery. Thus, another patient in this series had a detectable PSA that remained low and stable (0.4 ng/ml) and in spite of evidence of isolated local recurrence on immune scan, he continues to be managed expectantly. Previous reports suggest that PSA elevation occurring less than 2 y following radical prostatectomy in men with high grade cancer (Gleason score 8 or greater), seminal vesicle or lymph node involvement indicates high risk of metastatic disease 5 that is unlikely to be amenable to salvage therapy. 6 Although biopsies of the prostatic fossa after radical prostatectomy may need to be interpreted cautiously, scan sensitivity for recurrence has been estimated to be as high as 86%. 7 Bone scans are now routinely used for staging prostatic malignancy and evaluating bone metastases associated with advanced disease. Immunoscintigraphy may con- rm sites of bony involvement but may not reproduce the bone scan ndings. Immune scans sometimes fail to demonstrate sites of increased uptake on bone scan, which are non-speci c indicators of new bone formation. In addition, immune scans fail to detect bone metastases after treatment although uptake may persist on bone scan. The application of immunoscintigraphy in clinical practice merits more critical appraisal and prospective studies are in progress. CYT 356 is a monoclonal IgG antibody raised against the membrance bound prostatespeci c membrane antigen (PSMA) and labelled with indium-111. PSMA is expressed only in prostatic tissue and does not circulate in the bloodstream. The antibody itself is derived by mouse immunization against the LNCap human cell line and produced by a hybridoma. Tissue speci city of antibody binding has been demonstrated, 8 but the target epitope is intracellular and may only be accessible after internalisation of the antibody, or after cell death. 9 Its unique ability for tissue characterization contrasts conventional imaging techniques that identify alterations in macroscopic or compositional characteristics of normal structures (eg ultrasound, computerized tomography and magnetic resonance imaging), and the clinical information provided may be valuable when making therapeutic decisions. 4 Prostatic immunoscintigraphy using technetium-99m as the radiolabel also offers excellent imaging characteristics, as well as signi cant cost and radiation advantages over indium ± 12 51

6 52 Primary malignancy within the prostate is associated with substantially greater signal strength and uptake of antibody than benign prostatic tissue. Although this may be clearly evident in some scans, their interpretation is somewhat observer dependent and quantitative analysis (the `image surgery' technique 13 ) that would permit objective assessment of test sensitivity and speci city is not yet available. Immunoscintigraphy cannot at present reliably demonstrate the extent of the primary tumour or the presence of capsular invasion, and therefore its clinical application does not at present include predicting organcon ned cancer. This can however be estimated from digital rectal examination, serum PSA and biopsy grade. 14 Conclusion Immunoscintigraphy may demonstrate speci c binding to PSMA in soft tissue or lymph nodes in patients with prostate cancer, thereby offering a means of tumour staging based on immunological tissue characterization. This may be useful when planning de nitive therapy, assessing response to primary treatment, patterns of relapse or progression, and be particularly useful in men with a PSA and negative bone scan. When scans demonstrate unsuspected metastatic disease that would impact on therapeutic decisions, biopsy and histological con rmation should be sought whenever feasible before undertaking de nitive treatment. Acknowledgements We acknowledge the generous supply of antibody by the Cytogen Corporation. We thank the St Bartholomew's Foundation for Research for providing the laboratory space and the Imperial Cancer Research Fund for providing equipment and support for staff. References 1 Gregorakis AK, Holmes EH, Murphy GP. Prostate-speci c membrane antigen: current and future utility. Semin Urol Oncol 1998; 16: 2 ± Gervasi LA et al. Prognostic signi cance of lymph nodal metastases in prostate cancer. J Urol 1989; 142(2 Pt 1): 332 ± Murphy GP et al. Comparison of serum PSMA, PSA levels with results of Cytogen-356 ProstataScint scanning in prostatatic cancer patients. Prostate 1997; 33: 281 ± Levesque PE, Nieh PT, Zinman LN, Seldin DW, Libertino JA. Radiolabeled monoclonal antibody indium 111-labeled CYT-356 localizes extraprostatic recurrent carcinoma after prostatectomy. Urology 1998; 51: 978 ± Partin AW et al. Evaluation of serum prostate-speci c antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology 1994; 43: Cadeddu JA, Partin AW, DeWeese TL, Walsh PC. Long-term results of radiation therapy for prostate cancer recurrence following radical prostatectomy. JUrol1998; 159: 173 ± Haseman MK, Reed NL, Rosenthal SA. Monoclonal antibody imaging of occult prostate cancer in patients with elevated prostate-speci c antigen. Positron emission tomography and biopsy correlation. Clin Nucl Ned 1996; 21: 704 ± Barren RJ et al. Monoclonal antibody 7E11.C5 staining of viable LNCaP cells. Prostate 1997; 30: 65 ± Mardirossian G et al. Radiation absorbed dose from indium-111- CYT-356. J Nucl Med 1996; 37: 1583 ± Feneley MR et al. Prostatic radioimmunoscintigraphy: preliminary resultsusingtechnetium-labelled monoclonal antibody, CYT-351. Br JUrol1996; 77(3): 373 ± Chengazi VU, Feneley MRImaging prostate cancer with technetium-99m-7e11-c5.3 (CYT-351). J Nucl Med 1997; 38(5): 675 ± Stalteri MA et al. Site-speci c conjugation and labelling of prostate antibody 7E11C5.3 (CYT-351) with technetium-99m. Eur J Nucl Med 1997; 24: 651 ± Chengazi VU, Nimmon CC, Britton KE. Forward projection analysis and image surgery: an approach to quantitative tomography. In: Tomography in nuclear medicine, present status and future prospects. International Atomic Energy Agency; Vienna; 1996, pp. 31 ± Partin AW et al. Combination of prostate speci c antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer: a multi-institutional update. JAMA 1997; 277: 1445 ± 1451.