Steven P. Rowe

18F-DCFBC PET/CT for PSMA-Based Detection and Characterization of Primary Prostate Cancer

We previously demonstrated the ability to detect metastatic prostate cancer using N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-l-cysteine (18F-DCFBC), a low-molecular-weight radiotracer that targets the prostate-specific membrane antigen (PSMA). PSMA has been shown to be associated with higher Gleason grade and more aggressive disease. An imaging biomarker able to detect clinically significant high-grade primary prostate cancer reliably would address an unmet clinical need by allowing for risk-adapted patient management. Methods: We enrolled 13 patients with primary prostate cancer who were imaged with 18F-DCFBC PET before scheduled prostatectomy, with 12 of these patients also undergoing pelvic prostate MR imaging. Prostate 18F-DCFBC PET was correlated with MR imaging and histologic and immunohistochemical analysis on a prostate-segment (12 regions) and dominant-lesion basis. There were no incidental extraprostatic findings on PET suggestive of metastatic disease. Results: MR imaging was more sensitive than 18F-DCFBC PET for detection of primary prostate cancer on a per-segment (sensitivities of up to 0.17 and 0.39 for PET and MR imaging, respectively) and per-dominant-lesion analysis (sensitivities of 0.46 and 0.92 for PET and MR imaging, respectively). However, 18F-DCFBC PET was more specific than MR imaging by per-segment analysis (specificities of 0.96 and 0.89 for PET and MR imaging for corresponding sensitivity, respectively) and specific for detection of high-grade lesions (Gleason 8 and 9) greater than 1.0 mL in size (4/4 of these patients positive by PET). 18F-DCFBC uptake in tumors was positively correlated with Gleason score (ρ = 0.64; PSMA expression, ρ = 0.47; and prostate-specific antigen, ρ = 0.52). There was significantly lower 18F-DCFBC uptake in benign prostatic hypertrophy than primary tumors (median maximum standardized uptake value, 2.2 vs. 3.5; P = 0.004). Conclusion: Although the sensitivity of 18F-DCFBC for primary prostate cancer was less than MR imaging, 18F-DCFBC PET was able to detect the more clinically significant high-grade and larger-volume tumors (Gleason score 8 and 9) with higher specificity than MR imaging. In particular, there was relatively low 18F-DCFBC PET uptake in benign prostatic hypertrophy lesions, compared with cancer in the prostate, which may allow for more specific detection of primary prostate cancer by 18F-DCFBC PET. This study demonstrates the utility of PSMA-based PET, which may be used in conjunction with MR imaging to identify clinically significant prostate cancer.

Comparison of Prostate-Specific Membrane Antigen–Based 18F-DCFBC PET/CT to Conventional Imaging Modalities for Detection of Hormone-Naïve and Castration-Resistant Metastatic Prostate Cancer

Conventional imaging modalities (CIMs) have limited sensitivity and specificity for detection of metastatic prostate cancer. We examined the potential of a first-in-class radiofluorinated small-molecule inhibitor of prostate-specific membrane antigen (PSMA), N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-l-cysteine (18F-DCFBC), to detect metastatic hormone-naïve (HNPC) and castration-resistant prostate cancer (CRPC). Methods: Seventeen patients were prospectively enrolled (9 HNPC and 8 CRPC); 16 had CIM evidence of new or progressive metastatic prostate cancer and 1 had high clinical suspicion of metastatic disease. 18F-DCFBC PET/CT imaging was obtained with 2 successive PET scans starting at 2 h after injection. Patients were imaged with CIM at approximately the time of PET. A lesion-by-lesion analysis of PET to CIM was performed in the context of either HNPC or CRPC. The patients were followed with available clinical imaging as a reference standard to determine the true nature of identified lesions on PET and CIM. Results: On the lesion-by-lesion analysis, 18F-DCFBC PET was able to detect a larger number of lesions (592 positive with 63 equivocal) than CIM (520 positive with 61 equivocal) overall, in both HNPC and CRPC patients. 18F-DCFBC PET detection of lymph nodes, bone lesions, and visceral lesions was superior to CIM. When intrapatient clustering effects were considered, 18F-DCFBC PET was estimated to be positive in a large proportion of lesions that would be negative or equivocal on CIM (0.45). On follow-up, the sensitivity of 18F-DCFBC PET (0.92) was superior to CIM (0.71). 18F-DCFBC tumor uptake was increased at the later PET time point (∼2.5 h after injection), with background uptake showing a decreasing trend on later PET. Conclusion: PET imaging with 18F-DCFBC, a small-molecule PSMA-targeted radiotracer, detected more lesions than CIM and promises to diagnose and stage patients with metastatic prostate cancer more accurately than current imaging methods.

PET imaging of prostate-specific membrane antigen in prostate cancer: current state of the art and future challenges

Background:Prostate-specific membrane antigen (PSMA) is a cell surface enzyme that is highly expressed in prostate cancer (PCa) and is currently being extensively explored as a promising target for molecular imaging in a variety of clinical contexts. Novel antibody and small-molecule PSMA radiotracers labeled with a variety of radionuclides for positron emission tomography (PET) imaging applications have been developed and explored in recent studies.Methods:A great deal of progress has been made in defining the clinical utility of this class of PET agents through predominantly small and retrospective clinical studies. The most compelling data to date has been in the setting of biochemically recurrent PCa, where PSMA-targeted radiotracers have been found to be superior to conventional imaging and other molecular imaging agents for the detection of locally recurrent and metastatic PCa.Results:Early data, however, suggest that initial lymph node staging before definitive therapy in high-risk primary PCa patients may be limited, although intraoperative guidance may still hold promise. Other examples of potential promising applications for PSMA PET imaging include non-invasive characterization of primary PCa, staging and treatment planning for PSMA-targeted radiotherapeutics, and guidance of focal therapy for oligometastatic disease.Conclusions:However, all of these indications and applications for PCa PSMA PET imaging are still lacking and require large, prospective, systematic clinical trials for validation. Such validation trials are needed and hopefully will be forthcoming as the fields of molecular imaging, urology, radiation oncology and medical oncology continue to define and refine the utility of PSMA-targeted PET imaging to improve the management of PCa patients.

Prospective Evaluation of 99mTc-sestamibi SPECT/CT for the Diagnosis of Renal Oncocytomas and Hybrid Oncocytic/Chromophobe Tumors

UNLABELLED Nuclear imaging offers a potential noninvasive means of determining the histology of renal tumors. The aim of this study was to evaluate the accuracy of technetium-99m ((99m)Tc)-sestamibi single-photon emission computed tomography/x-ray computed tomography (SPECT/CT) for the differentiation of oncocytomas and hybrid oncocytic/chromophobe tumors (HOCTs) from other renal tumor histologies. In total, 50 patients with a solid clinical T1 renal mass were imaged with (99m)Tc-sestamibi SPECT/CT prior to surgical resection. Preoperative SPECT/CT scans were reviewed by two blinded readers, and their results were compared with centrally reviewed surgical pathology data. Following surgery, 6 (12%) tumors were classified as renal oncocytomas and 2 (4%) as HOCTs. With the exception of 1 (2%) angiomyolipoma, all other tumors were renal cell carcinomas (82%). (99m)Tc-sestamibi SPECT/CT correctly identified 5 of 6 (83.3%) oncocytomas and 2 of 2 (100%) HOCTs, resulting in an overall sensitivity of 87.5% (95% confidence interval [CI], 47.4-99.7%). Only two tumors were falsely positive on SPECT/CT, resulting in a specificity of 95.2% (95% CI, 83.8-99.4%). In summary, (99m)Tc-sestamibi SPECT/CT is a promising imaging test for the noninvasive diagnosis of renal oncocytomas and HOCTs. PATIENT SUMMARY We found that the imaging test (99m)Tc-sestamibi SPECT/CT can be used to accurately diagnose two types of benign kidney tumors. This test may be eventually used to help better evaluate patients diagnosed with a renal tumor.

Pearls and pitfalls in clinical interpretation of prostate-specific membrane antigen (PSMA)-targeted PET imaging

BackgroundThe rapidly expanding clinical adaptation of prostate-specific membrane antigen (PSMA)-targeted PET imaging in the evaluation of patients with prostate cancer has placed an increasing onus on understanding both the potential pearls of interpretation as well as limitations of this new technique. As with any new molecular imaging modality, accurate characterization of abnormalities on PSMA-targeted PET imaging can be accomplished only if one is aware of the normal distribution pattern, physiological variants of radiotracer uptake, and potential sources of false-positive and false-negative imaging findings. In recent years, a growing number of reports have come to light describing incidental non-prostatic benign or malignant pathologies with high uptake on PSMA-targeted PET imaging. In this review, we have summarized the published literature regarding the potential pearls and technical and interpretive pitfalls of this imaging modality. Knowledge of these limitations can increase the confidence of interpreting physicians and thus improve patient care.ConclusionsAs PSMA-targeted PET is expected to be evaluated in larger prospective trials, the dissemination of potential diagnostic pitfalls and the biologic underpinning of those findings will be of increased importance.

PSMA-Based Detection of Prostate Cancer Bone Lesions With 18F-DCFPyL PET/CT: A Sensitive Alternative to 99mTc-MDP Bone Scan and Na18F PET/CT?

Imaging of bone metastases in prostate cancer has traditionally involved planar Tc-methylene diphosphonate (Tc-MDP) bone scan with or without the use of supplemental tomographic imaging. More recently, NaF positron emission tomography/x-ray computed tomography (PET/CT) has been found to have improved sensitivity and specificity for sites of osseous metastatic involvement. Prostate-specific membrane antigen (PSMA) is a cell surface enzyme that is highly expressed in prostate cancer and has been explored as a target for prostate cancer imaging. In this case report, we found that PSMA-based PET/ CT with the small molecule F-DCFPyL detected a large number of bony lesions that were occult on Tc-MDP bone scan and NaF PET/CT. PSMA-targeted PET/CT may offer improved sensitivity by binding directly to tumor cells, as opposed to localizing to sites of bony reaction. This preliminary finding should be further explored in larger studies.

Initial Experience Using 99mTc-MIBI SPECT/CT for the Differentiation of Oncocytoma From Renal Cell Carcinoma

Purpose The differentiation of oncocytoma from renal cell carcinoma (RCC) remains a challenge with currently available cross-sectional imaging techniques. As a result, a large number of patients harboring a benign oncocytoma undergo unnecessary surgical resection. In this study, we explored the utility of 99mTc-MIBI SPECT/CT for the differentiation of these tumors based on the hypothesis that the large number of mitochondria in oncocytomas would lead to increased 99mTc-MIBI uptake. Patients and Methods In total, 6 patients (3 with oncocytoma and 3 with RCC) were imaged with 99mTc-MIBI SPECT/CT. Relative quantification was performed by measuring tumor-to-normal renal parenchyma background ratios. Results All 3 oncocytomas demonstrated radiotracer uptake near or above the normal renal parenchymal uptake (range of uptake ratios, 0.85–1.78). In contrast, the 3 RCCs were profoundly photopenic relative to renal background (range of uptake ratios, 0.21–0.31). Conclusions 99mTc-MIBI SPECT/CT appears to be of value in scintigraphically distinguishing benign renal oncocytoma from RCC.

Prediction of response to immune checkpoint inhibitor therapy using early-time-point 18F-FDG PET/CT imaging in patients with advanced melanoma

The purpose of this study was to evaluate 18F-FDG PET/CT scanning as an early predictor of response to immune checkpoint inhibitors (ICIs) in patients with advanced melanoma. Methods: Twenty patients with advanced melanoma receiving ICI prospectively underwent 18F-FDG PET/CT at 3 scan intervals: before treatment initiation (SCAN-1), at days 21–28 (SCAN-2), and at 4 mo (SCAN-3). This study was approved by the institutional review board, and informed consent was received from all patients who were enrolled between April 2012 and December 2013. Tumor response at each posttreatment time point was assessed according to RECIST 1.1, immune-related response criteria, PERCIST (PERCIST 1.0), and European Organization for Research and Treatment of Cancer (EORTC) criteria. Performance characteristics of each metric to predict best overall response (BOR) at ≥ 4 mo were assessed. Results: Twenty evaluable patients were treated with ipilimumab (n = 16), BMS-936559 (n = 3), or nivolumab (n = 1). BOR at ≥ 4 mo included complete response (n = 2), partial response (n = 2), stable disease (n = 1), and progressive disease (n = 15). Response evaluations at SCAN-2 using RECIST 1.1, immune-related response criteria, PERCIST, and EORTC criteria demonstrated accuracies of 75%, 70%, 70%, and 65%, respectively, to predict BOR at ≥ 4 mo. Interestingly, the optimal PERCIST and EORTC threshold values at SCAN-2 to predict BOR were >15.5% and >14.7%, respectively. By combining anatomic and functional imaging data collected at SCAN-2, we developed criteria to predict eventual response to ICI with 100% sensitivity, 93% specificity, and 95% accuracy. Conclusion: Combining functional and anatomic imaging parameters from 18F-FDG PET/CT scans performed early in ICI appears predictive for eventual response in patients with advanced melanoma. These findings require validation in larger cohorts.

Detection of 18F-FDG PET/CT Occult Lesions With 18F-DCFPyL PET/CT in a Patient With Metastatic Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is common with more than 60,000 new cases in the United States yearly. No curative therapies are available for metastatic RCC. Improved methods of imaging metastatic RCC would be of value in identifying sites of occult disease and potentially for judging response to therapy. A 58-year-old man with known metastatic clear cell RCC was imaged with both 18F-FDG and 18F-DCFPyL PET/CT. 18F-DCFPyL is a small molecule inhibitor of the prostate-specific membrane antigen (PSMA), a target known to be highly expressed on solid tumor neovasculature. Relative to 18F-FDG, 18F-DCFPyL identified more lesions and demonstrated higher tumor radiotracer uptake.

PSMA-Targeted 18F-DCFPyL PET/CT Imaging of Clear Cell Renal Cell Carcinoma: Results from a Rapid Autopsy

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is overexpressed by prostate cancer epithelial cells [1,2]. Despite the specificity implied by its name, PSMA is also expressed by endothelial cells within the neovasculature of a number of solid malignancies including clear cell renal cell carcinoma (ccRCC) [3–5]. Utilizing PSMA-targeted F-DCFPyL positron emission tomography/computed tomography (PET/ CT), we previously reported a sensitivity of 94.4% for detecting putative sites of disease in five patients with untreated metastatic ccRCC [6]. Notably, two (40%) of these patients had additional foci of radiotracer uptake (a total of 11 sites) that were suspicious for sites of metastases but lacked corresponding findings on conventional imaging. Similar results have since been reported using a gallium 68–labeled radiotracer targeting PSMA [7,8]. Combined, these data support a potential role for PSMA-targeted PET/CT to detect sites of otherwise clinically occult metastatic ccRCC. Available studies, however, have been limited by an inability to histologically sample PET-only detected lesions, leaving questions regarding the specificity of PSMA-targeted radiotracers for detecting true sites of disease. To address this, we imaged a patient with treatment-refractory ccRCC and, upon death, performed a rapid autopsy allowing for the histologic assessment of radiotracer-avid sites that were occult on conventional imaging. The patient was a 52-yr-old man with metastatic ccRCC refractory to multiple lines of systemic therapy. Following failure to respond to immunotherapy with nivolumab, the patient elected for hospice care and was imaged with whole-body F-DCFPyL PET/CT prior to death. Contemporaneously performed contrast-enhanced CT imaging of the chest, abdomen, and pelvis demonstrated 55 discrete sites of metastatic ccRCC. In total, 54 (98.1%) of these lesions had corresponding findings on PET/CT (Fig. 1). In addition, 12 sites of radiotracer uptake were observed that