Faculty Bibliography

In patients with carcinoma of the head and neck and of the esophagus, metabolic and functional imaging by PET with (18)F-FDG has a pivotal role in the evaluation of tumor response to therapy, specifically, in the prediction of progression-free survival and overall survival. Metabolic imaging allows the detection of biochemical changes within tumor cells as opposed to identifiable morphologic changes. Anatomic imaging modalities do not reliably differentiate between responders and nonresponders early during the course of follow-up. The correlation between histopathologic tumor response after preoperative therapy and clinical prognosis is well established for many cancers. Squamous carcinoma of the head and neck and esophageal carcinoma demonstrate avid (18)F-FDG uptake. For these cancers, (18)F-FDG PET parallels histopathologic findings in its ability to detect residual viable tumor; therefore, it is a valuable tool for the noninvasive assessment of histopathologic tumor response in advanced-stage cases after neoadjuvant therapy before surgery. Early determination of nonresponders is of prime importance, as timely therapy modification can be accomplished for patients who do not demonstrate a response to therapy. This determination is exceptionally important for head and neck and esophageal malignancies, both of which are known for their unfavorable prognosis, as early modifications in therapy regimens for nonresponders may improve patient outcome. There is now evidence that (18)F-FDG PET is a sensitive and specific method for determining therapy response and for providing important prognostic information for these cancers. Therefore, (18)F-FDG PET may change patient management and lead to improved survival for a selected group of patients with carcinoma of the head and neck and of the esophagus.

PURPOSE/OBJECTIVE:To determine the maximum-tolerated dose (MTD), toxicity, human antihuman antibody (HAHA) response, pharmacokinetics, organ dosimetry, targeting, and preliminary efficacy of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 ((90)Y-J591) in patients with androgen-independent prostate cancer (PC). PATIENTS AND METHODS/METHODS:Patients with androgen-independent PC and evidence of disease progression received indium-111-J591 for pharmacokinetic and biodistribution determinations followed 1 week later by (90)Y-J591 at five dose levels: 5, 10, 15, 17.5, and 20 mCi/m(2). Patients were eligible for up to three re-treatments if platelet and neutrophil recovery was satisfactory. RESULTS:Twenty-nine patients with androgen-independent PC received (90)Y-J591, four of whom were re-treated. Dose limiting toxicity (DLT) was seen at 20 mCi/m(2), with two patients experiencing thrombocytopenia with non-life-threatening bleeding episodes requiring platelet transfusions. The 17.5-mCi/m(2) dose level was determined to be the MTD. No re-treated patients experienced DLT. Nonhematologic toxicity was not dose limiting. Targeting of known sites of bone and soft tissue metastases was seen in the majority of patients. No HAHA response was seen. Antitumor activity was seen, with two patients experiencing 85% and 70% declines in prostate-specific antigen (PSA) levels lasting 8 and 8.6 months, respectively, before returning to baseline. Both patients had objective measurable disease responses. An additional six patients (21%) experienced PSA stabilization. CONCLUSION/CONCLUSIONS:The recommended dose for (90)Y-J591 is 17.5 mCi/m(2). Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation of (90)Y-J591 in the treatment of patients with PC.

Interpretation of positron emission tomographic (PET) scans in the absence of correlative anatomic information can be challenging. PET-computed tomography (CT) fusion imaging is a novel multimodality technology that allows the correlation of findings from two concurrent imaging modalities in a comprehensive examination. CT demonstrates exquisite anatomic detail but does not provide functional information, whereas 2-[fluorine 18]fluoro-2-deoxy-D-glucose (FDG) PET reveals aspects of tumor function and allows metabolic measurements. Subtle findings at FDG PET that might otherwise be disregarded or interpreted as physiologic variants may lead to detection of a malignant process after being correlated with simultaneously acquired CT findings. Alternatively, equivocal CT findings, which could represent malignant tumor, reactive changes, or fibrosis, can be clarified with the help of the additional metabolic information provided by concurrent FDG PET. Accurate interpretation of FDG PET scans requires a thorough knowledge of the normal physiologic distribution of FDG and of normal variants that may reduce the accuracy of PET studies, thereby significantly affecting patient treatment. Although in rare instances PET-CT cannot help resolve the diagnostic dilemma, it is enjoying widespread acceptance in the medical imaging community, usually allowing differentiation of physiologic variants from juxtaposed or mimetic neoplastic lesions and more accurate tumor localization.

Positron emission tomography (PET) imaging using [F-18]fluorodeoxyglucose (FDG) has become a useful imaging modality in the staging and treatment evaluation algorithm for lymphoma, providing unique metabolic information. Increased FDG uptake in lymphoma tumor masses is a function of increased anaerobic metabolism and longer residence time of FDG in malignant cells relative to most normal tissues. The information provided by FDG-PET appears to result in greater sensitivity compared to anatomic imaging modalities, particularly computed tomography (CT). Over several decades CT has been the principal imaging modality for the staging and restaging of lymphoma, although it can have significant shortcomings stemming from its sized-based criteria, particularly in the post-therapy setting. Gallium-67 (Ga-67) scintigraphy has played an important role in monitoring response to therapy; however, the sensitivity of Ga-67 depends on histologic subtype of lymphoma, size, and location of disease. Published results suggest that FDG-PET is superior to Ga-67 imaging and equal or superior to CT for the detection of nodal and extranodal lymphoma at initial staging. Furthermore, persistent FDG uptake during and after chemotherapy has a high sensitivity and specificity for prediction of subsequent relapse. While in some cases FDG-PET imaging can yield findings that prompt a change in treatment strategy, prospective studies are necessary to better establish the ability of routine FDG-PET imaging to impact therapeutic outcomes for patients with lymphoma.

PET is a unique form of diagnostic imaging that observes in vivo biologic changes using radiopharmaceuticals that closely mimic endogenous molecules. (18)F-FDG, which allows the evaluation of glucose metabolism, is the most commonly used tracer in oncology because of the practical half-life of (18)F (110 min), compared with other short-lived positron emitters. (18)F-FDG uptake in tumors is proportional to the glycolytic metabolic rate of viable tumor cells indicating the increased metabolic demand of tumors for glucose. (18)F-FDG PET significantly improves the accuracy of imaging tumors in initial staging, management of recurrent cancer, and monitoring of therapy response. The information provided by this technique is more sensitive and specific than that provided by anatomic imaging modalities. (18)F-FDG PET is particularly superior to CT or MRI in the ability to evaluate the effectiveness of various treatment regimens early during therapy or after therapy. In this review, we discuss the role of (18)F-FDG PET in evaluating the response to therapy and the impact of this information on patient management.

Positron emission tomography (PET) is a diagnostic imaging technique that allows identification of biochemical and physiologic alterations in tumors. Use of PET performed with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) significantly improves the accuracy of tumor imaging. In terms of oncologic applications, FDG PET has already gained widespread acceptance in the initial staging of cancer, management of recurrent cancer, and monitoring the response to therapy. With conventional imaging modalities, size criteria are used to distinguish between benign and malignant disease in lymph nodes; conversely, FDG PET is based on identification of fundamental aspects of tumor metabolism. FDG uptake in tumors is proportional to the metabolic rate of viable tumor cells, which have an increased demand for glucose. The high sensitivity and high negative predictive value of FDG PET in most malignant tumors enable this technique to play an even greater role in tumor management at initial staging and follow-up.

PURPOSE/OBJECTIVE:We performed an interim analysis of imaging data collected in 2 phase I radioimmunotherapy trials to determine the ability of monoclonal antibody (mAb) J591 directed to the extracellular domain of prostate specific membrane antigen (PSMA) to target sites of known metastatic prostate cancer accurately. MATERIALS AND METHODS/METHODS:Patients with progressing hormone independent prostate cancer were entered in 2 phase I dose finding trials with radiolabeled mAb J591. J591 is the first mAb targeting the extracellular domain of PSMA as well as the first de-immunized (humanized) mAb to PSMA to be tested in humans. These trials were primarily designed to assess dose limiting toxicity, maximum tolerated dose, pharmacokinetics and organ dosimetry. Planar gamma camera imaging studies obtained on the first 53 patients were reviewed and compared to sites of metastatic prostate cancer visualized on conventional imaging studies including bone scan, computerized tomography and/or magnetic resonance imaging. In 1 trial 29 patients received 111indium-J591 for imaging followed by 90yttrium-J591 for therapy. In the parallel trial 24 patients were treated with 177lutetium-J591, an isotope that can be imaged directly. RESULTS:Of 53 patients reviewed 46 (87%) had evidence of metastatic disease on conventional scans. Overall, of the 43 evaluable patients J591 accurately targeted bone and/or soft tissue lesions in 42 (98%). J591 accurately targeted bone lesions in 32 of 34 (94%) and soft tissue lesions in 13 of 18 (72%) evaluable patients. CONCLUSIONS:Radiolabeled J591 accurately targets bone and soft tissue metastatic prostate cancer sites, and may be useful for targeting therapeutic and/or diagnostic imaging agents.

For the last 60 years, hormonal therapy has been the cornerstone of treatment of metastatic prostate cancer. Unfortunately, hormonal therapy is purely palliative and improved systemic therapies are necessary. Monoclonal antibodies (mAbs) have proven valuable in the treatment of several diseases including cancer. mAbs act by focusing an immune response on or by targeting delivery of highly cytotoxic agents to the cancer cells without targeting normal cells. Prostate-specific membrane antigen (PSMA) has been identified as an ideal antigenic target in prostate cancer. PSMA is the most well-established, highly restricted prostate cancer cell surface antigen. It is expressed at high density on the cell membrane of all prostate cancers, and after antibody binding, the PSMA-antibody complex is rapidly internalized along with any payload carried by the antibody. J591 is the first IgG mAb developed to target the extracellular domain of PSMA, and it has been deimmunized (humanized) to allow repeated dosing in patients. Three phase I studies are in progress, two using the beta-emitting radiometals yttrium 90 and lutetium 177, and a third using a cytotoxin (DM1) linked to J591. Imaging of patients after they have received radiolabeled J591 demonstrates excellent tumor targeting.

PURPOSE/OBJECTIVE:Prostate specific membrane antigen (PSMA) is a cell surface peptidase highly expressed by malignant prostate epithelial cells and vascular endothelial cells of numerous solid tumor malignancies but not normal vascular endothelium in benign tissues or neoplastic epithelial cells of nonprostate malignancies. Monoclonal antibody (mAb) J591 recognizes the extracellular domain of PSMA. The current status of clinical trials using mAb J591 is reviewed. MATERIAL AND METHODS/METHODS:The mouse antibody was deimmunized by replacing murine immunoglobulin sequences with human immunoglobulin sequences, resulting in a nonimmunogenic antibody HuJ591. Results of completed and ongoing phase 1 and 2 clinical trials using mAb J591 are presented. RESULTS:A phase I clinical trial with murine J591 indicated that it possesses high affinity for prostate cancer metastases in bone and soft tissue. A phase I clinical trial showed that HuJ591 was well tolerated, demonstrated excellent targeting to disseminated prostate cancer sites and did not result in a host immune response to the antibody. A phase II clinical trial was initiated to study the efficacy of combining HuJ591 with low dose interleukin-2. Two phase I studies in patients with prostate cancer are in progress using the beta-emitting radiometals 90yttrium and 177lutetium linked via a DOTA chelate to HuJ591. Preliminary results from an ongoing phase I trial of 111indium labeled mAb HuJ591 in patients with advanced solid tumors showed that HuJ591 specifically targets nonprostate cancers. CONCLUSIONS:Early results of clinical studies indicate that mAb HuJ591 represents targeted therapy to PSMA and has therapeutic potential in prostate cancer and other urological and solid tumor malignancies.

BACKGROUND:The accuracy of fluorodeoxyglucose positron emission tomography (FDG-PET; dual-head camera with attenuation correction) and Ga-67 scintigraphy was compared to identify disease sites in patients with Hodgkin disease (HD) and intermediate and high-grade non-Hodgkin lymphoma (NHL) at initial diagnosis or clinical recurrence. METHODS:Fifty-one contemporaneous FDG-PET and Ga-67 scintigraphies were performed on patients with NHL (35 intermediate grade, 3 high grade) or HD (13 patients). Sites of disease were correlated on a site-by-site basis on FDG-PET and Ga-67 images. Tumor-to-background (T/B) ratios were obtained for both techniques. Discordant FDG-PET and Ga-67 findings were correlated with computed tomography findings or clinical evaluation including repeat FDG-PET scans obtained after therapy. RESULTS:Fluorodeoxyglucose positron emission tomography was positive at all 158 sites in 51 patients compared with 113 sites in 41 positive studies with Ga-67 scintigraphy (single positron emission computed tomography [SPECT] and/or planar images). In 44 patients who had complete Ga-67 SPECT data on all tumor sites, FDG-PET was positive at 126 sites and Ga-67 SPECT was positive at 81 sites. Ga-67 SPECT failed to demonstrate disease at 45 sites (35.7%). In 10 of 44 patients, Ga-67 SPECT completely failed to detect any disease at 22 of 45 sites (17.5%) and partially identified disease sites at 23 of 45 sites (18.2%) in 11 patients regardless of the tumor site and histology. In these patients, the lesions measured between 0.6 and 14.0 cm by CT. Fluorodeoxyglucose positron emission tomography revealed higher stage disease in 13 patients compared with Ga-67 imaging. Tumor-to-background ratios were statistically different between the two techniques with higher ratios obtained with FDG-PET (P < 0.0001). CONCLUSIONS:In imaging aggressive lymphoma and HD before therapy, FDG-PET has significantly higher site and patient sensitivity than Ga-67 scintigraphy (100% vs. 71.5% and 100% vs. 80.3%, respectively). The change in disease stage by FDG-PET may result in a change in therapy strategy.