Steve Cho

Biodistribution, Tumor Detection, and Radiation Dosimetry of 18F-DCFBC, a Low-Molecular-Weight Inhibitor of Prostate-Specific Membrane Antigen, in Patients with Metastatic Prostate Cancer

Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-l-cysteine (18F-DCFBC) could image an experimental model of PSMA-positive PCa using PET. Here, we describe the initial clinical experience and radiation dosimetry of 18F-DCFBC in men with metastatic PCa. Methods: Five patients with radiologic evidence of metastatic PCa were studied after the intravenous administration of 370 MBq (10 mCi) of 18F-DCFBC. Serial PET was performed until 2 h after administration. Time–activity curves were generated for selected normal tissues and metastatic foci. Radiation dose estimates were calculated using OLINDA/EXM 1.1. Results: Most vascular organs demonstrated a slow decrease in radioactivity concentration over time consistent with clearance from the blood pool, with primarily urinary radiotracer excretion. Thirty-two PET-positive suspected metastatic sites were identified, with 21 concordant on both PET and conventional imaging for abnormal findings compatible with metastatic disease. Of the 11 PET-positive sites not identified on conventional imaging, most were within the bone and could be considered suggestive for the detection of early bone metastases, although further validation is needed. The highest mean absorbed dose per unit administered radioactivity (μGy/MBq) was in the bladder wall (32.4), and the resultant effective dose was 19.9 ± 1.34 μSv/MBq (mean ± SD). Conclusion: Although further studies are needed for validation, our findings demonstrate the potential of 18F-DCFBC as a new positron-emitting imaging agent for the detection of metastatic PCa. This study also provides dose estimates for 18F-DCFBC that are comparable to those of other PET radiopharmaceuticals such as 18F-FDG.

First-in-Man Evaluation of 2 High-Affinity PSMA-Avid Small Molecules for Imaging Prostate Cancer

This phase 1 study was performed to determine the pharmacokinetics and ability to visualize prostate cancer in bone, soft-tissue, and the prostate gland using 123I-MIP-1072 and 123I-MIP-1095, novel radiolabeled small molecules targeting prostate-specific membrane antigen. Methods: Seven patients with a documented history of prostate cancer by histopathology or radiologic evidence of metastatic disease were intravenously administered 370 MBq (10 mCi) of 123I-MIP-1072 and 123I-MIP-1095 2 wk apart in a crossover trial design. 123I-MIP-1072 was also studied in 6 healthy volunteers. Whole-body planar and SPECT/CT imaging was performed and pharmacokinetics studied over 2–3 d. Target-to-background ratios were calculated. Absorbed radiation doses were estimated using OLINDA/EXM. Results: 123I-MIP-1072 and 123I-MIP-1095 visualized lesions in soft tissue, bone, and the prostate gland within 0.5–1 h after injection, with retention beyond 48 h. Target-to-background ratios from planar images averaged 2:1 at 1 h, 3:1 at 4–24 h, and greater than 10:1 at 4 and 24 h for SPECT/CT. Both agents cleared the blood in a biphasic manner; clearance of 123I-MIP-1072 was approximately 5 times faster. 123I-MIP-1072 was excreted in the urine, with 54% and 74% present by 24 and 72 h, respectively. In contrast, only 7% and 20% of 123I-MIP-1095 had been renally excreted by 24 and 72 h, respectively. Estimated absorbed radiation doses were 0.054 versus 0.110 mGy/MBq for the kidneys and 0.024 versus 0.058 mGy/MBq for the liver, for 123I-MIP-1072 and 123I-MIP-1095, respectively. Conclusion: 123I-MIP-1072 and 123I-MIP-1095 detect lesions in soft tissue, bone, and the prostate gland at as early as 1–4 h. These novel radiolabeled small molecules have excellent pharmacokinetic and pharmacodynamic profiles and warrant further development as diagnostic and potentially when labeled with 131I therapeutic radiopharmaceuticals.

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.

Tandem dosing of samarium-153 ethylenediamine tetramethylene phosphoric acid with stem cell support for patients with high-risk osteosarcoma

Samarium‐153 ethylenediamine tetramethylene phosphoric acid (153Sm‐EDTMP) is a radiopharmaceutical that has been used to treat osteosarcoma. The authors conducted a phase 2 study to test safety and response of high‐risk osteosarcoma to tandem doses of 153Sm‐EDTMP and to determine correlation between radiation delivered by low and high administered activities.

Uptake of 18F-DCFPyL in Paget’s Disease of Bone, an Important Potential Pitfall in Clinical Interpretation of PSMA PET Studies

Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging is an emerging technique for evaluating patients with prostate cancer (PCa) in a variety of clinical contexts. As with any new imaging modality, there are interpretive pitfalls that are beginning to be recognized. In this report, we describe the findings in a 63-year-old male with biochemically recurrent PCa after radical prostatectomy who was imaged with 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid ([18F]DCFPyL), a small-molecule inhibitor of PSMA. Diffuse radiotracer uptake was noted throughout the sacrum, corresponding to imaging findings on contrast-enhanced computed tomography (CT), bone scan, and pelvic magnetic resonance imaging consistent with Pagets disease of bone. The uptake of [18F]DCFPyL in Pagets disease most likely results from hyperemia and increased radiotracer delivery. In light of the overlap in patients affected by PCa and Pagets disease, it is important for nuclear medicine physicians and radiologists to be aware of the potential for this diagnostic pitfall when interpreting PSMA PET/CT scans. Correlating findings on conventional imaging such as diagnostic CT and bone scan can help confirm the diagnosis.

Molecular Imaging of Urogenital Diseases

There is an expanding and exciting repertoire of PET imaging radiotracers for urogenital diseases, particularly in prostate cancer, renal cell cancer, and renal function. Prostate cancer is the most commonly diagnosed cancer in men. With growing therapeutic options for the treatment of metastatic and advanced prostate cancer, improved functional imaging of prostate cancer beyond the limitations of conventional CT and bone scan is becoming increasingly important for both clinical management and drug development. PET radiotracers, apart from ¹⁸F-FDG, for prostate cancer are ¹⁸F-sodium fluoride, ¹¹C-choline, and ¹⁸F-fluorocholine, and (¹¹C-acetate. Other emerging and promising PET radiotracers include a synthetic l-leucine amino acid analogue (anti-¹⁸F-fluorocyclobutane-1-carboxylic acid), dihydrotestosterone analogue (¹⁸F-fluoro-5α-dihydrotestosterone), and prostate-specific membrane antigen-based PET radiotracers (eg, N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-¹⁸F-fluorobenzyl-l-cysteine, ⁸⁹Zr-DFO-J591, and ⁶⁸Ga [HBED-CC]). Larger prospective and comparison trials of these PET radiotracers are needed to establish the role of PET/CT in prostate cancer. Although renal cell cancer imaging with FDG-PET/CT is available, it can be limited, especially for detection of the primary tumor. Improved renal cell cancer detection with carbonic anhydrase IX (CAIX)-based antibody (¹²⁴I-girentuximab) and radioimmunotherapy targeting with ¹⁷⁷Lu-cG250 appear promising. Evaluation of renal injury by imaging renal perfusion and function with novel PET radiotracers include p-¹⁸F-fluorohippurate, hippurate m-cyano-p-¹⁸F-fluorohippurate, and rubidium-82 chloride (typically used for myocardial perfusion imaging). Renal receptor imaging of the renal renin-angiotensin system with a variety of selective PET radioligands is also becoming available for clinical translation.

Detection and localization of carcinoma within the prostate using high resolution transrectal gamma imaging (TRGI) of monoclonal antibody directed at prostate specific membrane antigen (PSMA)—Proof of concept and initial imaging results

PURPOSE Molecular imaging methods may identify primary prostate cancer foci and potentially guide biopsy and optimal management approaches. In this exploratory study, safety and first human imaging experience of a novel solid state endocavity transrectal gamma-imaging (TRGI) device was evaluated. METHODS Twelve patients received 5 ± 0.5 mCi In-111 capromab pendetide (ProstaScint) intravenously and the prostate of each was imaged 4 days later transrectally using an endoluminal cadmium zinc telluride (CZT)-based compact gamma camera (ProxiScan™, Hybridyne Imaging Technologies, Inc.). Immediate and 5-7-day post imaging safety assessments were performed. In those patients with a prostate cancer diagnosis (N=10), single photon emission computed tomography (SPECT-CT) and magnetic resonance imaging (MRI) of the pelvis were also acquired. Images were reviewed and sites of suspected cancer were localized by prostate quadrant by consensus of two nuclear medicine physicians. Pathology from TRUS biopsy, or surgical pathology following prostatectomy (N=3) when available, served as the gold standard. RESULTS There were no serious adverse events associated with TRGI. No focal signal was detected in patients without a diagnosis of prostate cancer (N=2). Of 40 quadrants evaluated in the cancer cohort (N=10), 22 contained malignancy. In 8 of these 10 patients, the most focal site of uptake on TRGI corresponded to a prostatic quadrant with biopsy-proven malignancy. In 6 cancer-containing quadrants, TRGI was positive where SPECT-CT was negative; MRI showed a detectable abnormality in only 1 of these 6 quadrants. Qualitative image review of the planar TRGI images for prostate cancer localization was severely limited in some cases by scatter artifact within the vicinity of the prostate gland arising from physiologic urine and blood pool activity from nearby structures. CONCLUSIONS TRGI is a safe imaging method that can potentially detect radiopharmaceutical uptake of primary prostate cancer and facilitate prostatic quadrant - localization of cancer. Further investigation of this technology is warranted.

A Phase 1 Study of 131I-CLR1404 in Patients with Relapsed or Refractory Advanced Solid Tumors: Dosimetry, Biodistribution, Pharmacokinetics, and Safety

Introduction 131I-CLR1404 is a small molecule that combines a tumor-targeting moiety with a therapeutic radioisotope. The primary aim of this phase 1 study was to determine the administered radioactivity expected to deliver 400 mSv to the bone marrow. The secondary aims were to determine the pharmacokinetic (PK) and safety profiles of 131I-CLR1404. Methods Eight subjects with refractory or relapsed advanced solid tumors were treated with a single injection of 370 MBq of 131I-CLR1404. Whole body planar nuclear medicine scans were performed at 15–35 minutes, 4–6, 18–24, 48, 72, 144 hours, and 14 days post injection. Optional single photon emission computed tomography imaging was performed on two patients 6 days post injection. Clinical laboratory parameters were evaluated in blood and urine. Plasma PK was evaluated on 127I-CLR1404 mass measurements. To evaluate renal clearance of 131I-CLR1404, urine was collected for 14 days post injection. Absorbed dose estimates for target organs were determined using the RADAR method with OLINDA/EXM software. Results Single administrations of 370 MBq of 131I-CLR1404 were well tolerated by all subjects. No severe adverse events were reported and no adverse event was dose-limiting. Plasma 127I-CLR1404 concentrations declined in a bi-exponential manner with a mean t½ value of 822 hours. Mean Cmax and AUC(0-t) values were 72.2 ng/mL and 15753 ng•hr/mL, respectively. An administered activity of approximately 740 MBq is predicted to deliver 400 mSv to marrow. Conclusions Preliminary data suggest that 131I-CLR1404 is well tolerated and may have unique potential as an anti-cancer agent. Trial Registration ClinicalTrials.gov NCT00925275

Effect of Patient Arm Motion in Whole-Body PET/CT

Arm motion during whole-body PET/CT acquisition is not uncommon and can give rise to striking cold artifacts on PET images. We investigated the mechanisms that underlie these artifacts and proposed a potential solution. Methods: A phantom experiment based on 5 clinical cases of suspected arm motion was designed. The experiment involved a central 20-cm-diameter 68Ge/68Ga cylinder simulating the neck and 2 peripheral 10-cm-diameter 18F cylinders simulating arms. After motion-free CT and PET on a whole-body PET/CT system, the position of the arms was altered so as to introduce different amounts of misalignment. Twenty sequential PET scans were acquired in this position, alternating between 2-dimensional (2D) and 3-dimensional (3D) acquisition, as the 18F decayed. Decay of 18F in the arms, while the activity in the 68Ge/68Ga cylinder remained approximately constant, allowed the relative impact of scatter and attenuation-correction errors to be determined. Results: Image artifacts were largely confined to the local region of motion in 2D but extended throughout the affected slices in 3D, where they manifested as a striking underestimation of radiotracer concentration that became more significant with increasing misalignment. For 3D, scatter-correction error depended on activity in the arms, but for typical activity concentrations scatter-correction error was more significant than attenuation-correction error. 3D image reconstruction without scatter correction substantially eliminated these artifacts in both phantom and patient images. Conclusion: Reconstruction artifacts due to patient arm motion can be substantial and should be recognized because they can affect both qualitative and quantitative assessment of PET.