Current Clinical Applications of the In-capromab Pendetide Scan (ProstaScint® Scan, Cyt-356)

Technique Update

TECHNIQUE UPDATE Current Clinical Applications of the 111In-capromab Pendetide Scan (ProstaScint® Scan, Cyt-356) Misop Han, MD, Alan W. Partin, MD, PhD James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD Prostate-specific antigen (PSA) has been extremely helpful in the detection of new or recurrent prostate cancer. However, localization of the recurrent tumor has been challenging with currently available radiographic modalities. The 111In-capromab pendetide scan was developed to diagnose accurately and, more importantly, localize and stage a new or recurrent prostate cancer. Studies suggest that the 111In-capromab pendetide scan can provide more accurate staging of clinically localized prostate cancer prior to staging lymphadenectomy or definitive therapy. It can also provide valuable information when local adjuvant radiation therapy is considered in men with biochemical cancer recurrence following radical prostatectomy. [Rev Urol. 2001;3(4):165–171] © 2001 MedReviews, LLC Key words: 111In-capromab pendetide scan • ProstaScint • Prostate cancer • Soft-tissue lesions • Radiolabeled monoclonal antibody • Lymph node • Prostatic fossa F or men with newly diagnosed, clinically localized prostate cancer, there exists a possibility of extraprostatic disease (local or regional) prior to definitive treatment. Several studies have demonstrated that over 30% of men will experience biochemical recurrence of prostate cancer after surgery with long-term (more than 10 years) follow-up.1–7 For patients who have already undergone definitive treatment, the localization of recurrent tumor, evidenced by an elevation of PSA, is difficult unless the tumor burden is large enough to be detected on conventional radiographic studies or digital rectal examination and prostatic fossa biopsy. Computed tomography (CT) and magnetic resonance imaging (MRI) have both failed to address the need for a sensitive and specific modality that can accurately localize prostate cancer. Prior to the development of the 111In-capromab pendetide scan, several attempts were made to use radiolabeled monoclonal antibodies against prostate-related antigens to localize prostate cancer.8 111In-labeled monoclonal antibodies against PSA were demonstrated to have poor sensitivity in limited early clinical trials. VOL. 3 NO. 4 2001 REVIEWS IN UROLOGY 165 Current Clinical Applications of the 111 In-capromab Pendetide Scan continued rent tumors following surgery, which can be one of the indications for the 111In-capromab pendetide scan. This review article discusses the potential areas of application of the 111Incapromab pendetide, scan based on recent clinical studies, as well as its limitations. Preliminary Studies Antibody 7E11-C5.3 Gamma-emitting radionuclide GYK-DTPA (Linker) Indium 111 Figure 1. The schematic diagram of an immunoconjugate of the 7E11-C5.3 monoclonal antibody (CYT-356) used in the 111In-capromab pendetide scan. 111 In-labeled monoclonal antibodies against prostatic acid phosphatase (PAP) showed better imaging results but poor results in detecting soft-tissue lesions, including the primary lesion. Also, when these earlier assays were used, 50% of men developed human anti-mouse antibodies (HAMA) that may cause adverse effects and potentially limit the effectiveness of repeat immunoscans or immunotherapies. Therefore the search continued for a radiographic study with a better localization of prostate cancer and minimal potential side effects. The 111In-capromab pendetide scan, also known as the ProstaScint® scan (Cytogen Corporation, Princeton, NJ) utilizes a radiolabeled monoclonal antibody directed toward an intracellular epitope (N-terminus) of the prostate-specific membrane antigen (PSMA) molecule.9,10 PSMA is a 120-kD transmembrane glycoprotein with unknown physiologic function.11 It is expressed on prostate cells (both benign and malignant) as well as on the surface of new blood vessels induced by neoplastic growth.12 PSMA was recognized using the 7E11-C5.3 monoclonal antibody, generated against the LNCaP human 166 VOL. 3 NO. 4 2001 prostate adenocarcinoma cell line.13 An immunoconjugate of the 7E11-C5.3 monoclonal antibody (CYT-356) is used in the 111In-capromab pendetide scan (Figure 1).10 Data suggest that the 7E11-C5.3 antibody has the ability to bind the intracellular epitope (the first 6 amino acid residues) of the PSMA expressed in viable prostate cancer cells during in vivo imaging studies.14 Over the past two decades, the detection, treatment, and monitoring of prostate cancer have undergone In a phase I study, 40 men with known distant prostate cancer metastases underwent an 111In-capromab pendetide scan.10 There were no adverse reactions. Bony metastases were found in 21 of 38 men (55.3%), including 12 of 14 men who were receiving concomitant hormonal therapy. Soft-tissue lesions were confirmed in 4 of 6 men. Subsequently, Babaian and colleagues studied 19 men with prostate cancer who underwent preoperative 111In-capromab pendetide scan and pelvic CT or MRI, prior to bilateral pelvic lymph node dissection.15 Eight men had lymph node involvement of prostate cancer, with the size ranging from 1 mm to 15 mm. Four men with lymph node metastases had positive 111In-capromab pendetide scan results, with the detection threshold with respect to nodal size of 5 mm or Detection, treatment, and monitoring of prostate cancer have undergone remarkable improvements. remarkable improvements. PSA is widely used and incorporated in the detection, staging, and monitoring of this common disease. Radical prostatectomy has become the most common treatment modality for localized prostate cancer, with excellent treatment outcomes. However, a significant proportion of men experience biochemical evidence of recurrence following surgery. There is an urgent need for better localization of recur- REVIEWS IN UROLOGY greater. There were four false-negative images with lesions of 3 mm or less. There were also two false-positive 111In-capromab pendetide scans. The overall sensitivity and specificity of the 111In-capromab pendetide scan were 44% and 86%, respectively. The authors concluded that a single dose of CYT-356 antibody is safe and capable of detecting soft-tissue nodal disease. Kahn and colleagues studied 27 Current Clinical Applications of the men with rising serum PSA level (>0.8 ng/mL) following radical retropubic prostatectomy (RRP) with negative bone scan and transrectal ultrasound.16 Of 22 men with one or more lesions found on the 111In-capromab pendetide scan, with needle biopsy, CT, or MRI, 11 men were confirmed to have recurrent prostate cancer. Fourteen men were found to have prostatic fossa lesions on the 111In-capromab pendetide scan. Thirteen of them underwent a single fine-needle biopsy of the prostatic ≥ 10 ng/mL, Gleason score on biopsy of 4 + 3, 8–10, or large palpable [≥T2b] disease), a thorough preoperative lymph node staging is important because there is a strong association between lymph node involvement and the presence of distant metastases. Presently, there exist several ways to evaluate lymph nodes for metastatic prostate cancer. Pelvic lymph node dissection is usually performed during radical retropubic prostatectomy or using a laparoscopic approach. Image-guided biopsy of a Radical prostatectomy has become the most common treatment modality for localized prostate cancer. fossa, and in eight (62%) the biopsy was positive for prostate cancer. Sodee and colleagues studied 15 men with rising serum PSA (0.2 to 82.5 ng/mL) following RRP and bilateral pelvic lymphadenectomy.17 Fourteen men had evidence of residual prostatic bed (10) or metastatic prostate cancer (7 parailiac or para-aortic lymph nodes) on the 111In-capromab pendetide scan. Interestingly, all 14 men had negative preoperative radiographic abdominal and pelvic CT or MRI, and 13 had normal preoperative bone scan. Only one man underwent prostatic fossa biopsy, which was negative. In summary, these preliminary studies demonstrate that the CYT-356 antibody used in the 111In-capromab pendetide scan is safe and able to detect soft-tissue prostate cancer lesions. In addition, they suggest that the 111In-capromab pendetide scan might be useful for detection of postsurgical recurrence. Clinical Applications Detection of lymph node involvement prior to surgery. In many men presenting with localized prostate cancer and high-risk criteria (eg, PSA lymph node can also be performed if it can be localized with CT and is of sufficient size for a needle biopsy. Conventional radiographic studies have been shown to be unreliable unless the nodal tumor burden is large (~1 cm). Bone scan can detect the bony metastasis of prostate cancer; however, it cannot detect other soft-tissue metastases. The 111In-capromab pendetide scan can be used to detect positive lymph nodes prior to radical prostatectomy. Hinkle and colleagues studied 48 men 111 In-capromab Pendetide Scan metastases on pathologic examination. The sensitivity and specificity of the 111In-capromab pendetide scan in this study were 75% and 86%, respectively. The combined sensitivity and specificity of conventional radiographic modalities (CT, MRI, and transrectal ultrasound) were only 20% and 68%, respectively. Subsequently, Manyak and colleagues studied 152 patients with high risk for lymph node metastases and negative or equivocal imaging with CT or MRI who underwent 111Incapromab pendetide scans prior to radical prostatectomy and pelvic lymph node dissection without previous therapy for their disease.19 Pathologic examination revealed 64 (42%) men with lymph node metastases. The 111In-capromab pendetide scan detected 40 of 64 (63%) men with lymph node involvement (38/40 correct on the appropriate side). The 111In-capromab pendetide scan was more sensitive (63%) compared to CT (4%) or MRI (15%) in detecting lymph node involvement of prostate cancer. There were 88 men without lymph node involvement. The specificity of the 111In-capromab pendetide scan was 72% (63/88). Interestingly, 14 of 25 men with negative lymph nodes on pathology and positive There is a strong association between lymph node involvement and the presence of distant metastases. with high risk for lymph node metastasis who underwent 111In-capromab pendetide scans prior to radical prostatectomy, bilateral pelvic lymph node dissection, and additional exploration and biopsy of scan-positive extraprostatic regions.18 The 111Incapromab pendetide scan showed evidence of lymph node involvement in 19 (40%) men, and 15 (32%) of those men had positive lymph node 111 In-capromab pendetide scan experienced PSA progression following RRP, suggesting that the true specificity of the 111In-capromab pendetide scan is even higher than 72%. Long-term analysis of this cohort is lacking at present. In addition, logistic regression analysis of this population of men with high risk of nodal metastases demonstrated that the result of the 111In-capromab pendetide VOL. 3 NO. 4 2001 REVIEWS IN UROLOGY 167 Current Clinical Applications of the scan was the most powerful single predictor of metastatic disease when compared to PSA and Gleason score.19 Meanwhile, Polascik and colleagues compared several clinical staging algorithms and the 111In-capromab pendetide scan in predicting lymph node metastases in men who had a 111In-capromab pendetide scan prior to undergoing staging pelvic lymphadenectomy.20 In their analysis, the 111In-capromab pendetide scan result was a strong, independent predictor for lymph node metastases. They also concluded that combining the currently available staging algorithms with 111In-capromab pendetide scan improves the predictive power to determine lymph node involvement. In summary, in men newly diagnosed with prostate cancer and with high risk of lymph node involvement, the 111In-capromab pendetide scan can detect lymph node metastasis not detectable by CT or MRI. The 111In-capromab pendetide scan can provide additional information on lymph node metastasis status prior to staging lymphadenectomy, independent of PSA level or Gleason score. Even though long-term data are lacking at present, the currently available studies suggest that the 111In-capromab pendetide scan can provide more accurate staging of clinically localized prostate cancer prior to staging lymphadenectomy or definitive therapy and will be beneficial to guide the patients and physicians in choosing appropriate therapy. Imaging for recurrent disease in the prostatic fossa following definitive therapy. The localization of recurrent prostate cancer following surgery is beneficial prior to delivery of adjuvant therapy. If the recurrent disease resides within the prostatic fossa, adjuvant radiation therapy to that area is reasonable as well as effective. However, if the recurrence is beyond the prostatic fossa, systemic 168 VOL. 3 NO. 4 2001 111 In-capromab Pendetide Scan continued therapy is preferred. Fine-needle biopsy of the prostatic fossa and clinical evidence of a large palpable nodule have been used to diagnose local recurrence, yet neither can readily diagnose tumors beyond the prostatic fossa. Therefore an accurate localization of recurrent prostate cancer by 111In-capromab pendetide scan can be very helpful in decisionmaking regarding adjuvant therapy. Levesque and colleagues studied 48 men who had biochemical evidence of recurrence (PSA > 0.8 ng/mL) following radical prostatectomy, with a mean PSA of 28.7 ng/mL.21 The 111In-capromab pendetide scan to salvage radiation therapy to the prostatic fossa. Durable complete response to radiation therapy (PSA < 0.3 ng/mL for more than 6 months and at the time of last follow-up) was achieved in 16 of 23 men (70%) with a normal scan outside of the prostatic fossa. In a subsequent reevaluation of this study with a longer mean follow-up (35 months), 61% of the men experienced durable complete response to radiation, suggesting that the response to the radiation was prolonged, not temporary.23 In contrast, of nine men who had positive scan outside of the prostatic fossa, only two (22%) had durable Present studies suggest that the 111In-capromab pendetide scan can detect recurrent disease in the prostatic fossa following surgery. was positive in 38 men. Interestingly, 3 men had localization to prostatic fossa only, whereas 35 men had evidence of disease beyond the prostatic fossa. Thirteen men underwent adjuvant external-beam radiation therapy to prostatic fossa following an 111In-capromab pendetide scan. Two of six men (33%) with positive 111In-capromab pendetide scan outside of the radiation therapy field had good response (PSA < 0.2 ng/mL) to radiation therapy. Meanwhile, five of seven men (71%) with negative 111In-capromab pendetide scan outside of the radiation therapy field had good response to radiation. Kahn and colleagues performed the most intriguing study of imaging recurrent prostate cancer in the prostatic fossa following surgery using a 111In-capromab pendetide scan.22 They studied 32 men who had biochemical evidence of recurrence (PSA > 0.3 ng/mL) following radical prostatectomy, with a mean follow up of 13 months. The 111In-capromab pendetide scans were performed prior REVIEWS IN UROLOGY complete response to salvage radiation therapy, even with longer follow-up. Therefore, a durable complete response rate to salvage radiation therapy in postsurgical patients was higher in men lacking evidence of extraprostatic fossa disease by 111Incapromab pendetide scan. Kahn and colleagues also studied 181 men with interpretable 111Incapromab pendetide scans.24 Of 181 men, 158 had PSA under 1.0 ng/mL and positive DRE or PSA over 1.0 ng/mL and negative or equivocal work-up (bone scan, DRE, TRUS, CT, or MRI of abdomen and pelvis). The authors compared the results of 111Incapromab pendetide scan with the results of a single needle biopsy of the prostatic fossa. Although a controversial endpoint, when a prostatic fossa needle biopsy was used as a “gold standard," the sensitivity and specificity of the 111In-capromab pendetide scan were 49% and 71%, respectively. In summary, present studies suggest that the 111In-capromab pendetide scan can detect recurrent disease in Current Clinical Applications of the the prostatic fossa following surgery, but they are inconclusive because there are no good “gold standards" to define local recurrence. However, if there is a suspicion of local recurrence, the 111In-capromab pendetide scan can provide valuable information, especially when local salvage radiation therapy is considered. Metastatic pattern of prostate cancer from autopsy studies and 111In-capromab pendetide scan. Detection of occult extraprostatic fossa disease before or after initial local therapy is a challenging task. According to conventional wisdom, prostate cancer initially metastasizes to pelvic lymph nodes. However, some studies have suggested that prostate cancer can metastasize via alternate lymphatic drainage patterns. For example, Saitoh and colleagues performed an autopsy study on 753 men with metastatic prostate cancer. 25 There were 476 men (63%) with lymph node involvement. The authors suggested several alternate lymphatic drainage patterns of prostate carcinoma, with most involving the paraaortic lymph node chain without evidence of pelvic lymph node involvement. Subsequently, Bubendorf and colleagues from Basel, Switzerland, performed a larger autopsy study demonstrating metastatic patterns of prostate cancer.26 In an autopsy study of 1589 patients with prostate cancer, lymphatic or hematogenous metastases were seen in 631 men (39.7%) when histologic analysis was performed only in cases of suspicious macroscopic findings or gross abnormality. Of 415 men with lymphatic involvement of prostate cancer, many had para-aortic (75%) or pelvic (55%) lymph node involvement. Of 336 men with hematogenous metastases, 90% involved bone and 46% involved lung. Interestingly, the metastatic pat- tern of prostate cancer from these autopsy studies is consistent with the detection pattern of the 111In-capromab pendetide scan of men with frequent para-aortic lymph node involvement.24 In a large study by Kahn and colleagues, 34% of men had a positive 111In-capromab pendetide scan in the prostatic fossa, and 42% had a positive scan outside of the prostatic fossa.24 The common sites of positive 111In-capromab pendetide scan outside the prostatic fossa were para-aortic/mesenteric lymph nodes (23%), 111 In-capromab Pendetide Scan Even though the antibodies were generally well tolerated, adverse reactions occurred in 4% to 5% on the initial and repeat injection of the antibody. Hyperbilirubinemia, hypotension, and hypertension occurred in 1% of patients. Elevated liver enzymes, pruritus, fever, rash, and headache occurred in less than 1% of patients in clinical trials. The epitope on PSMA recognized by the monoclonal antibody, 7E11-C5, is expressed on the inner or cytoplasmic side of the plasma membrane.14 Even though the antibodies were generally well tolerated, adverse reactions occurred in 4% to 5% on the initial and repeat injection of the antibody. pelvic lymph nodes (22%), and bone (4%). The results from both autopsy and 111In-capromab pendetide scan studies of men with metastatic prostate cancer suggest that prostate cancer has an alternative lymph node metastasis pattern. Detection of metastases in para-aortic as well as pelvic lymph nodes using 111Incapromab pendetide scan would be helpful in deciding between local versus systemic therapy for men with newly diagnosed or recurrent prostate cancer. Limitations In spite of the clinical uses for the 111In-capromab pendetide scan, there are several possible limitations concerning this new technique. First, the murine monoclonal antibodies used in the 111In-capromab pendetide scan (7E11P) can generate (though infrequently) human anti-mouse antibody (HAMA). HAMA formation occurred in 8% after the initial and 19% following the second infusion of antibodies. However, HAMA formation was transient and not correlated with any adverse effect in both the initial and repeat infusions.27 However, viable prostate cancer cells uptake and specifically bind 7E11-C5 (accessible to intracellular epitopes of prostatic cancer cells in vivo).9 Lastly, “pooling" of antibodies can occur in unrelated tumor or nontumor tissue with high blood content, such as bowel and vascular structures.27,28 To minimize false-positive interpretations of the scan, repeat studies are performed 72 to 120 hours following initial injection of radiolabeled antibodies to allow clearance of the isotopes from the vascular and intestinal structures. Interpretation of the scan requires extensive training, because the pelvic anatomy is not well delineated on this type of scan. The radiologist must become familiar with the detailed anatomy of the male pelvis to interpret the normal isotope uptake patterns. As a result, the manufacturer of the 111In-capromab pendetide scan requires certification in a special training program (Partners In Excellence [PIE]) so that the nuclear medicine physician can interpret the scan properly.29 In summary, the adverse effects of the 111In-capromab pendetide scan, VOL. 3 NO. 4 2001 REVIEWS IN UROLOGY 169 Current Clinical Applications of the 111 In-capromab Pendetide Scan continued CT/MRI overlay may also improve the accuracy of the 111In-capromab pendetide scan29 (Figure 2). Another area of promising research is the therapeutic use of the monoclonal antibodies conjugated to cytotoxic drugs, toxins, or therapeutic radionuclides, such as labeling of CYT-365 with 90Yttrium.30,31 A successful therapeutic use of these conjugated monoclonal antibodies may provide more options to treat patients with prostate cancer. Conclusions Figure 2. The 111In-capromab pendetide scan and computed tomography coregistration. From the Cytogen ProstaScint scan slide review series. “Image of the Year” award at the Society of Nuclear Medicine meeting from Drs. Zhenghong Lee and D. Bruce Sodee of the University Hospitals of Cleveland/Case Western University. Used with permission from Cytogen Corporation. though rare, include HAMA formation and other physiologic changes, such as blood pressure fluctuation and hepatic enzyme elevation. Other limitations of the 111In-capromab pendetide scan include the “pooling" of antibodies and decreased sensitivity of antibodies used in the scan as a result of cytoplasmic location of the epitope. In addition to these challenges, the radiologist should undertake extensive training to interpret the 111In-capromab pendetide scan appropriately. Future Directions There are efforts further to improve or enhance the 111In-capromab pendetide scan by different techniques. One example is dual isotope imaging, involving simultaneous In-111 monoclonal antibody and Tc-99m RBC SPECT acquisition to subtract dynamically the vascular component (Tc-99m RBC) from the prostate and lymph node component (In-111 monoclonal antibody). Also, three-dimensional image reconstructions and The antibody used in the 111Incapromab pendetide scan is safe, with only mild adverse effects (4% to 5% on the initial and repeat injection). The 111In-capromab pendetide scan can be used prior to staging pelvic lymphadenectomy or definitive therapy to detect lymph node metastases in men with high probability of lymph node involvement, as determined by an elevated PSA, high Gleason score, or advanced clinical stage. It can complement currently used staging algorithms and provide better detection of lymph node metastases than conventional radiographic modalities such as CT or MRI. The 111In-capromab pendetide scan can also provide valuable informa- Main Points • Computed tomography and magnetic resonance imaging have failed to address the need for a sensitive and specific modality that can accurately localize prostate cancer. • A significant proportion of men experience biochemical evidence of recurrence following surgery. • Conventional radiographic studies have been shown to be unreliable unless the nodal tumor burden is large. • The 111In-capromab pendetide (ProstaScint) scan utilizes a radiolabeled monoclonal antibody directed toward an intracellular epitope (N-terminus) of the prostate-specific membrane antigen (PSMA) molecule. • The 111In-capromab pendetide scan can be used to detect positive lymph nodes prior to radical prostatectomy. • Studies suggest that the 111In-capromab pendetide scan can provide more accurate staging of clinically localized prostate cancer prior to staging lymphadenectomy or definitive therapy. • The murine monoclonal antibodies used in the 111In-capromab pendetide scan can generate human anti-mouse antibody, but this is transient and was not correlated with any adverse effect in both initial and repeat infusions. • Hyperbilirubinemia, hypotension, and hypertension occurred in 1% of patients studied; elevated liver enzymes, pruritus, fever, rash, and headache occurred in less than 1% of patients in clinical trials. • The manufacturer of the 111In-capromab pendetide scan requires certification in a special training program. 170 VOL. 3 NO. 4 2001 REVIEWS IN UROLOGY Current Clinical Applications of the tion especially when local adjuvant radiation therapy is considered in patients with biochemical cancer recurrence following radical prostatectomy. Studies have demonstrated that adjuvant radiation therapy is more effective when there is evidence of local recurrence without metastasis according to the 111In-capromab pendetide scan. As more long-term data accumulate, the 111In-capromab pendetide scan can be incorporated into the current array of tests and algorithms to help better stage and localize prostate cancer. [Note: Dr. Partin acts as a consultant for Cytogen Corporation.] 8. 9. 10. 11. 12. 13. References 1. 2. 3. 4. 5. 6. 7. Catalona WJ, Smith DS. 5-year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer [see comments]. J Urol. 1994;152:1837–1842. Catalona WJ, Smith DS. Cancer recurrence and survival rates after anatomic radical retropubic prostatectomy for prostate cancer: intermediate-term results. J Urol. 1998;160:2428–2434. Han M, Partin AW, Pound CR, et al. 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