The role of (111)In Capromab Pendetide (Prosta-ScintR) immunoscintigraphy in the management of prostate cancer.

(111)In Capromab Pendetide (ProstaScintR) is a whole murine antibody that is reactive with prostate specific membrane antigen (PSMA), a glycoprotein on the surface of normal and abnormal prostate epithelium. It has proven to be of great value in assisting management decisions in prostate cancer patients who initially present with high risk for metastatic spread, or who develop a picture of recurrent disease after surgery or radiation therapy. Patterns of metastatic lymphatic spread have correlated well with autopsy reports in the literature. Unfortunately, other imaging study and/or histologic confirmation of scintigraphic findings has been difficult to obtain. Prostascint's role in predicting durable complete response (DCR) in postoperative patients having salvage radiotherapy to their prostate fossa is very promising. Further investigative work in larger patient populations is needed to confirm these early results.

Utility of capromab pendetide (ProstaScint) imaging in the management of prostate cancer.

PURPOSE: Capromab pendetide (ProstaScint) is an indium In 111 ((111)In)-labeled monoclonal antibody to prostate-specific membrane antigen (PSMA) used to image prostate cancer. The appropriate techniques for obtaining images with this modality and the appropriate clinical indications for this study are in the process of being optimized. MATERIALS AND METHODS: From 1994 to 2000, 631 monoclonal antibody imaging studies with (111)In capromab pendetide were performed. The accuracy and utility of this modality in the primary staging of patients with disease at high risk of metastasis and patients with recurrent or residual disease after primary therapy were evaluated. RESULTS: In high-risk patients evaluated for risk of lymph node metastases prior to pelvic lymph node dissection, capromab pendetide imaging was found to have a positive predictive value (PPV) of 62%, negative predictive value (NPV) of 72%, sensitivity of 62%, and specificity of 72%. In patients evaluated with capromab pendetide imaging for prostatic fossa recurrence using prostatic fossa needle biopsy as the gold standard, capromab pendetide imaging was found to have a PPV of 50%, NPV of 70%, sensitivity of 49%, and specificity of 71%. CONCLUSIONS: The sensitivity and NPV of (111)In capromab pendetide imaging are better than those of computed tomography and magnetic resonance imaging for detection of soft-tissue and nodal metastases from prostate cancer. The utility of this modality has been demonstrated in the primary staging of patients with disease at high risk of metastasis. Patients with recurrent or residual disease after primary therapy also may benefit from capromab pendetide imaging prior to selection of salvage therapy. Innovative methods for the use of capromab pendetide imaging in radiation therapy treatment planning are under development.

Capromab Pendetide imaging of prostate cancer.

Capromab Pendetide imaging illustrates the successful translation of monoclonal antibody technology from the laboratory to the clinic. It provides a means of identifying otherwise occult soft tissue metastases in patients with adenocarcinoma of the prostate. When utilized with other clinical, pathological and laboratory findings, Capromab Pendetide imaging enables more accurate disease staging and monitoring than is afforded by other imaging modalities such as CT and MRI. In the primary disease setting Capromab Pendetide imaging should be reserved for use in patients with negative bone scans who are at high risk for metastatic disease based on such factors as advanced clinical stage, high Gleason score and significantly elevated serum PSA or alkaline phosphatase. Due to low sensitivity for small-volume disease, a negative Mab scan may not eliminate the need for a staging lymph node dissection but should encourage further consideration of local treatment options. Capromab Pendetide should be used with caution in patients at low risk for metastatic disease. Positive scan findings in low risk patients should be confirmed before altering the treatment plan since some false positive scans should be anticipated in a population with low disease prevalence. Capromab Pendetide imaging has not been shown to be reliable in determining the local extent of the primary tumor but new techniques involving co-registration of SPECT and CT images show promise in this regard. In the patient with recurrent disease following primary therapy, the predictive value of Capromab Pendetide imaging of the prostate or prostate fossa is limited, particularly following RT. Its more important role in this setting is to identify lymph node metastases in the high risk patient with a negative bone scan who might otherwise be a candidate for local salvage therapy. A large prospective study is needed for confirmation, but preliminary data suggest that Capromab Pendetide imaging is helpful in identifying those patients with PSA elevation after radical prostatectomy who are most likely to benefit from salvage RT. As with any imaging technique, Capromab Pendetide has strengths and weaknesses that must be understood to maximize patient benefit by utilizing the scan in clinical settings where it is most likely to be useful and least likely to be misleading. Capromab Pendetide is a technically demanding procedure best performed and interpreted at sites with experience and expertise.

Whole-body PET imaging with [18F]fluorodeoxyglucose in management of recurrent colorectal cancer.

HYPOTHESIS: Metabolic imaging by positron emission tomography (PET) using [18F]fluorodeoxyglucose will be more accurate than anatomic imaging by computed tomography (CT) for detection of recurrent colorectal cancer. More accurate staging of recurrent tumor by PET will lead to more appropriate management decisions. DESIGN: Prospective blinded study comparing PET with CT, using histologic diagnosis, serial CT imaging, and clinical follow-up as criterion standards, with a fully blinded, retrospective reinterpretation of PET studies. Changes in diagnosis resulting from PET findings were correlated with subsequent treatment and surgical findings. Potential cost savings resulting from use of PET for preoperative staging were calculated. SETTING: Private practice in an outpatient tertiary referral center. PATIENTS: A group of 155 consecutive patients with imaging for diagnosis or staging of recurrent colorectal cancer. Twenty-one patient (14%) were excluded due to lack of a criterion standard. Computed tomographic scans were available for comparison for 115 patients. RESULTS: Positron emission tomographic scan sensitivity and specificity were 93% and 98%, respectively, compared with 69% and 96% for CT. Ninety-five percent confidence intervals for the differences between the modalities were 16% to 32% for sensitivity and 1% to 5% for specificity. The sensitivity of both modalities varied with anatomic site of recurrence. Positron emission tomographic scans were true positive in 12 (67%) of 18 patients with elevated serum carcinoembryonic antigen levels and negative CT findings. In 23 (29%) of 78 preoperative studies in which CT showed a single site of recurrence, PET showed tumor at additional sites. At surgery, nonresectable, PET-negative tumor was found in 7 (17%) of 42 patients who had PET evidence of localized recurrence only. Potential savings resulting from demonstration of nonresectable tumor by PET were calculated at $3003 per preoperative study. CONCLUSIONS: Positron emission tomography was more sensitive and specific than CT for detection of recurrent colorectal cancer. Preoperative detection of nonresectable tumor by PET may avoid unnecessary surgery, and thereby reduce the cost of patient treatment.

Comparison of clinical staging algorithms and 111indium-capromab pendetide immunoscintigraphy in the prediction of lymph node involvement in high risk prostate carcinoma patients.

BACKGROUND: The pretherapy prediction of occult lymph node involvement and the avoidance of otherwise futile and potentially morbid definitive local therapy is paramount in men with newly diagnosed prostate carcinoma. To identify patients with prostate carcinoma who likely have lymph node involvement and would benefit from staging lymphadenectomy prior to definitive local therapy, the authors compared the ability of several predictive staging algorithms and a radiolabeled monoclonal antibody scan to predict lymphatic metastases prior to treatment. METHODS: Between August 1991 and June 1994, 198 men with clinical T2 or T3 classified (TNM) prostate carcinoma (bone scan negative) who were at high risk of lymph node involvement underwent a 111In-capromab pendetide scan prior to staging lymphadenectomy. Several predictive models based on preoperative prostate specific antigen level, biopsy Gleason score, and clinical stage were selected to predict those men having a > or =20% probability of lymph node involvement. The ability to predict pathologic stage using several clinical algorithms and the monoclonal antibody scan was compared with pathologic examination of the lymph nodes. RESULTS: Overall, 39% of the pelvic lymph node specimens were positive for metastatic disease by pathologic analysis. Published algorithms predicting lymph node metastases had a positive predictive value (PPV) ranging from 40.5% to 46.6% and an area under the receiver operating characteristic curve (AUC) ranging from 0.52 to 0.61. The monoclonal antibody scan had a PPV of 66.7% and an AUC of 0.71. The differences between the PPV and the AUC for the individual clinical algorithms when compared with immunoscintigraphy were statistically significant. Combining the radiolabeled monoclonal antibody scan with clinical predictive models, a PPV of up to 72.1% could be obtained. CONCLUSIONS: These data suggest that the PPVs for the clinical predictive algorithms are similar and that the PPV of the radiolabeled monoclonal antibody scan alone or in combination with the algorithms has additional value in predicting lymph node involvement in prostate carcinoma patients at high risk of regional disease spread. These algorithms and the 111In-capromab pendetide scan may be used for the appropriate selection of candidates for definitive local therapy in men with clinically localized prostate carcinoma and significant risk of lymph node involvement.

111Indium-capromab pendetide in the evaluation of patients with residual or recurrent prostate cancer after radical prostatectomy. The ProstaScint Study Group.

PURPOSE: Standard diagnostic methods are limited for detecting distant metastases in patients with prostate cancer in whom the only evidence of disease after radical prostatectomy is a detectable prostate specific antigen (PSA) level. We evaluated the role of immunoscintigraphy with the radiolabeled monoclonal antibody, 111indium ((111)In)-capromab pendetide, to differentiate between local and distant recurrence in this patient population. MATERIALS AND METHODS: We enrolled 183 men who had undergone radical prostatectomy in whom PSA later increased. Gamma camera images were acquired twice after infusion of a single dose of (111)In-capromab pendetide. RESULTS: Immunoscintigraphy revealed disease in 108 of 181 patients (60%) with interpretable scans. The antibody was localized most frequently to the prostatic fossa (34% of the cases), abdominal lymph nodes (23%) and pelvic lymph nodes (22%). Of the 181 men the scan localized the antibody outside the prostatic fossa in 42%. Half of the positive localizations in the fossa were confirmed by biopsy. CONCLUSIONS: These findings suggest that immunoscintigraphy with (111)In-capromab pendetide can assist in determining the extent of disease in patients who have increasing PSA after prostatectomy.

Radioimmunoscintigraphy with In-111-labeled capromab pendetide predicts prostate cancer response to salvage radiotherapy after failed radical prostatectomy.

PURPOSE: We investigated the ability of In-111-capromab pendetide to separate patients who have failed radical prostatectomy into categories of those who would versus those who would not respond to salvage radiotherapy. METHODS: Prostate-specific antigen (PSA) levels in 32 men with prostate cancer who had failed radical prostatectomy and had undergone a whole-body In-111-capromab pendetide scan were followed-up for 13 months (median) after salvage radiotherapy to the pelvis. A logistic regression model was used to determine whether the scan findings, as well as other clinical variables, were associated with a durable complete response (DCR), a nondurable response (NDR), or no response (NR). RESULTS: Sixteen of 23 (70%) men with a normal scan outside the prostatic fossa achieved a DCR after salvage radiotherapy versus two of nine (22%) who had a positive scan outside the prostate fossa and pelvis (P = .0225, Fisher's exact test). Predicted probability (95% confidence interval [CI]) that a DCR would be obtained with a normal scan was 0.88 (0.55 to 0.98); for men with a positive scan limited to the prostatic fossa it was 0.62 (0.42 to 0.79); and for men with a positive scan outside the pelvis it was 0.27 (0.09 to 0.58). No other variables before radiotherapy showed a significant association with the DCR rate. CONCLUSION: Salvage radiotherapy is statistically more likely to lead to a durable complete PSA response in men with prostate cancer who have failed radical prostatectomy and have a negative In-111-capromab pendetide scan outside the pelvis as compared with those who have a positive scan.

Monoclonal antibody imaging of occult prostate cancer in patients with elevated prostate-specific antigen. Positron emission tomography and biopsy correlation.

The utility of monoclonal antibody (MAb) imaging for detection of occult recurrent prostate cancer was investigated in 14 patients with elevated serum prostate-specific antigen at least 3 months after therapy. All were imaged with capromab pendetide (CYT-356) and subsequently had biopsies of the prostate bed. Ten also had PET scans with F-18 fluorodeoxyglucose. Ten MAb scans were positive for tumor in the prostate bed and eight showed lymph node metastases. Six of the seven patients with positive biopsies had positive MAb scans, one had a negative scan. Three of the seven patients with negative biopsies had negative MAb scans, four had positive scans. Of the six patients with positive biopsies who had PET scans, one was positive, five were negative. Two of four patients with negative biopsies had negative positron emission tomography scans, two were positive. MAb imaging is superior to PET scan for identifying recurrent disease in the prostate bed. Assuming no false-negative biopsies, the positive predictive values for MAb and PET scan are 60% and 33%, negative predictive values are 75% and 29% and sensitivities are 86% and 17%. Additional investigation is necessary to determine if MAb uptake in lymph nodes is predictive of metastatic disease.

Cost-effectiveness of PET imaging in clinical oncology.

To be cost-effective, PET must be diagnostically accurate and effective in improving management without increasing treatment cost. To evaluate diagnostic accuracy, we performed prospective evaluations of whole-body PET imaging in staging of non-small-cell lung cancer (99 patients), detection of recurrent colorectal cancer (57 patients), diagnosis of metastatic melanoma (36 patients), and staging of advanced head and neck cancer (29 patients). In each case, PET was more accurate than anatomic imaging for determination of the presence and extent of tumor and demonstration of nonresectable disease. PET was also more accurate than conventional imaging in staging Hodgkin's disease (30 patients). We evaluated the management impact of PET retrospectively, by reviewing the treatment records of 72 patients with solitary pulmonary nodules or non-small-cell lung cancer, 68 patients with known or suspected recurrent colorectal cancer, 45 patients with known or suspected metastatic melanoma, and 29 patients with advanced head and neck tumors. PET improved patient management by avoiding surgery for nonresectable tumor and for CT abnormalities that proved to be benign by PET imaging. For determining cost impact, the costs of surgical procedures were determined from Medicare reimbursement rates, and the cost of a PET study was taken to be $1800. The savings from contraindicated surgical procedures exceeded the cost of PET imaging by ratios of 2:1 to 4:1, depending on the indication. PET was decisively more accurate and cost-effective than anatomic imaging by CT, combining improved patient care with reduced cost of management.

Staging non-small cell lung cancer by whole-body positron emission tomographic imaging.

BACKGROUND: A need exists for an accurate, noninvasive means of staging non-small cell lung cancer. METHODS: A prospective evaluation of regional and whole-body positron emission tomography (PET) imaging for staging lung cancer was carried out in 99 patients. Mediastinal PET and computed tomography findings were compared with results of surgical staging in 76 patients. Those PET and computed tomography findings that indicated possible distant metastasis were compared with biopsy results and the results of clinical and imaging follow-up. RESULTS: Sensitivity and specificity for the diagnosis of N2 disease were 83% and 94% for PET and 63% and 73% for computed tomography, respectively. Positron emission tomography showed previously unsuspected distant metastasis in 11 patients (11%), with no demonstrated false-positive results. Normal PET findings were obtained at distant sites of computed tomography abnormality in 19 patients (19%). Clinical and imaging follow-up in 14 of these patients showed no evidence of metastasis. In 1 case, the PET result proved to be falsely negative. CONCLUSIONS: Imaging with PET was more accurate than computed tomography for diagnosis of mediastinal and distant metastasis. Detection of unsuspected metastatic disease by PET may permit reduction in the number of thoracotomies performed for nonresectable disease.

Monoclonal antibody imaging of recurrent and metastatic prostate cancer.

In summary, this agent is safe for administration and more accurate than any currently available imaging modality for the detection of extraprostatic metastases. This agent is still under investigation and some day may aid urologists in the evaluation of prostate cancer by improving preoperative staging and demonstration of advanced disease and postoperative localization of recurrent disease. Improved staging and localization will reduce unnecessary tests and treatment that will lead to reduced morbidity, better management, earlier detection, and intervention in advanced disease and improved cost-effectiveness.

Gamma probe location of 111indium-labeled B72.3: an extension of immunoscintigraphy.

Eight colorectal and 5 ovarian cancer patients were evaluated with preoperative immunoscintigraphy and intraoperative gamma probe detection of 111indium-labeled monoclonal antibody B72.3. Immunoscintigraphy detected the presence of tumor in every patient shown to have tumor at surgery. There was one false-positive scan. A total of 21 pathologically verified lesions were identified at surgery in the 11 patients with tumor. Immunoscintigraphy localized 12 (57%) and intraoperative gamma probe detection located 17 (81%) of the lesions. Intraoperative probe detection located 6 of 8 lesions smaller than 1 cm and 3 lesions that were not identified on initial surgical exploration. The gamma probe offers information that is complementary to immunoscintigraphy in that (1) it aids the surgeon in locating intra- and extra-abdominal lesions previously identified by immunoscintigraphy, (2) it locates lesions too small to be seen by immunoscintigraphy alone, (3) it locates lesions that otherwise might be missed at surgery, and (4) it provides objective evidence for adequacy of surgical resection of cancer in the abdominal cavity.

Radioimmunodetection of occult carcinoembryonic antigen-producing cancer.

This study evaluates the ability of 111In-labeled anti-carcinoembryonic antigen (CEA) monoclonal antibody (Mab) ZCE-025 to detect sites of occult cancer in patients with elevated serum CEA who have negative or equivocal CT scans. One hundred forty patients suspected of having occult cancer were evaluated. Except for elevated CEA levels, all had negative work-ups, including negative or inconclusive CT scans. Eighty-two patients (59%) had positive scans and 58 (41%) had negative scans. Seventy-five of the 82 patients with positive scans had confirmation of at least one Mab-positive lesion (91% positive predictive value). Thirty-eight of the 58 patients with negative scans had negative follow-up (66% negative predictive value). The Mab scan correctly identified at least one site of tumor in 75 of the 95 patients with recurrent or metastatic disease (79% sensitivity) and correctly predicted the absence of disease in 38 of 45 patients (84% specificity).

Metabolizable 111In chelate conjugated anti-idiotype monoclonal antibody for radioimmunodetection of lymphoma in mice.

The relative biological properties of 111In-labeled monoclonal antibodies (MoAb) coupled with a conventional bifunctional chelate (BC) and a new, enzyme metabolizable, bifunctional chelate (BCM) were investigated. A rat IgG2a MoAb against idiotype from a mouse B-cell lymphoma was utilized. Mice bearing B-cell lymphomas in the subcutaneous tissues of the flank were given IV-injections of labeled MoAb and imaged or killed for organ counting at 24 h or 48 h. Rat anti-dinitrophenyl IgG2a MoAb and non-specific polyclonal mouse IgG were used as controls. Compared to BC, the use of BCM resulted in a substantial decrease in blood background activity, a shorter biological half-life and an increase in tumor to blood ratio at the expense of a moderate decrease in absolute tumor uptake. The versatile chemistry of these C-1 substituted bifunctional chelates provides a variety of possible enzyme cleavable moieties for further investigation.

Chelate conjugates of monoclonal antibodies for imaging lymphoid structures in the mouse.

Radiolabeling of a mouse monoclonal antibody (MoAb) specific for the mouse histocompatibility alloantigen IAk expressed by the B lymphocytes of BALB/k and C3H mice but not BALB/c mice was performed by mixing the chelate-labeled anti (alpha) IAk MoAb with purified, no-carrier-added 111In citrate. Labeling efficiency was 85-95%, and the labeled alpha IAk MoAb retained its antigen binding properties in vitro and in vivo. The organ, spleen, and lymph node distribution of intravenously and subcutaneously administered 111In alpha IAk MoAb was compared in mice, two IAk positive and one IAk negative strains, and to 125I alpha IAk MoAb in one IAk positive strain. The 111In alpha IAk MoAb was more stable in vivo compared to 125I alpha IAk MoAb, as shown by a much slower excretion and a higher absolute uptake in lymph nodes and spleen. Lymph node to blood ratio was increased twofold by intravenous anti-EDTA MoAb. Subcutaneous injection permitted clear images of the tiny lymph nodes in the mouse. Potential clinical applications of 111In alpha lymphocyte MoAb include localization of normal lymph nodes and T & B cell leukemias and lymphomas, as well as detecting lymphatic metastases of other cancers. Therapy may also be possible using MoAbs labeled with beta-emitting metal ions such as yttrium-90.

Indium 111 WBC scan in local and systemic fungal infections.

We describe two patients-one with a systemic fungal infection and one with a localized form-who had strikingly abnormal indium 111 leukocyte (WBC) scans. The patient with systemic disease had an abnormal WBC scan before lesions became clinically apparent.