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.

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.

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.

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.

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.

UNLABELLED:Early identification of chemotherapy-refractory lymphoma patients provides a basis for alternative treatment strategies. Metabolic imaging with (18)F-FDG PET offers functional tissue characterization that is useful for assessing response to therapy. Our objective was to determine the predictive value of (18)F-FDG PET early during chemotherapy (after 1 cycle) and at the completion of chemotherapy for subsequent progression-free survival (PFS) in patients with aggressive non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). METHODS:(18)F-FDG PET (dual-head coincidence camera with attenuation correction) was performed before and after 1 cycle of chemotherapy on 30 patients (17 NHL, 13 HD; mean age, 52.3 +/- 16.0 y). For 23 of the 30 patients, (18)F-FDG PET data were also obtained after the completion of chemotherapy. The patients had a median follow-up of 19 mo (range, 18-24 mo). Follow-up of PFS was compared between patients with positive and negative (18)F-FDG PET results obtained after the first cycle of chemotherapy and at the completion of chemotherapy. RESULTS:Positive (18)F-FDG PET results obtained both after the first cycle and at the completion of therapy were associated with a shorter PFS (median, 5 and 0 mo, respectively) than were negative (18)F-FDG PET results (PFS medians not reached). A statistically significant difference in PFS between positive and negative (18)F-FDG PET results was obtained both after the first cycle and at the completion of chemotherapy (P < or = 0.001). The PFS and (18)F-FDG PET results obtained after the first cycle correlated better than those obtained after the completion of chemotherapy (r(2) = 0.45 vs. 0.17). (18)F-FDG PET had more false-negative results after the last cycle (6/17 cases, or 35%) than after the first cycle (2/13 cases, or 15%). Thus, (18)F-FDG PET had greater sensitivity and positive predictive values after the first cycle (82% vs. 45.5% and 90% vs. 83%, respectively) than after the last cycle. CONCLUSION/CONCLUSIONS:(18)F-FDG PET after 1 cycle of chemotherapy is predictive of 18-mo outcome in patients with aggressive NHL and HD and may earlier identify patients who would benefit from more intensive treatment programs.

Monoclonal antibodies (mAbs) to prostate-specific antigens, such as PSMA, have great potential as diagnostic and therapeutic tools in the management of advanced prostate cancer. PSMA is a very attractive target for mAb-based imaging. It is expressed by virtually all prostate cancers and its expression is further increased in poorly differentiated, metastatic, and hormone-refractory carcinomas. The ProstaScint scan (Cytogen, Princeton, NJ), based on the mAb 7E11-C5.3, is currently approved for the imaging of prostate cancer in soft tissue but is not approved for imaging bone metastases. It appears superior to conventional imaging studies for soft-tissue disease but has limitations attributed to its intracellular binding site on PSMA. Overcoming this limitation, new mAbs to the extracellular domain of PSMA have been developed. The radioisotopes, (111)Indium, (90)Yttrium, and (177)Lutetium have been conjugated to one such mAb, J591. Radioimmunoscintigraphy with this immunoconjugate has demonstrated excellent tumor targeting of prostate cancer sites not only in soft tissue but also in bone.

The success of chemotherapy in the treatment of malignancies may be limited by cellular mechanisms leading to drug resistance. In hematological malignancies, mechanisms leading to the development of multidrug resistance (MDR) include overexpression of the membrane-based export pump P-glycoprotein (Pgp) and the MDR-associated protein (MRP). Recently, the overexpression of the lung-resistance protein (LRP) has also been associated with reduced intracellular drug accumulation. A major problem in assessing the significance of the expression of these resistance proteins in clinical MDR has been the variability of detection techniques either at the mRNA or protein level. Currently, the detection of resistance proteins relies heavily on antibody and cDNA probes, and these methods may not be informative about the in vivo function of Pgp, MRP, or LRP. Nuclear medicine imaging techniques such as single-photon emission tomography (SPECT) and positron emission tomography (PET) have been evaluated for noninvasive determination of the presence and the function of Pgp- and MRP-mediated transport systems. Technetium 99m ((99m)Tc)-sestamibi, an agent in clinical use for myocardial perfusion and tumor imaging, is recognized as a substrate for Pgp and MRP, and has been used to visualize Pgp expression. (99m)Tc-tetrofosmin is also a substrate for the Pgp efflux pump mechanism and is used to evaluate Pgp function in in vitro and in vivo studies. Recently, radiopharmaceuticals including carbon 11-labeled colchicine, verapamil, and daunorubicin have been used in cell line and animal studies for the evaluation of Pgp-mediated transport functions using PET technology. Preliminary results suggest that the potential to detect MDR in tumors prior to or after exposure to chemotherapeutic agents exists in imaging using either (99m)Tc-labeled compounds and SPECT or positron emitting compounds and PET.