Detection of failure patterns using advanced imaging in patients with biochemical recurrence following low-dose-rate brachytherapy for prostate cancer.

PURPOSE/OBJECTIVE(S): This study describes the pattern of failure in patients with biochemical (BCR) recurrence after low-dose-rate (LDR) brachytherapy as a component of definitive treatment for prostate cancer. METHODS: Patients with BCR after LDR brachytherapy ± external beam radiation therapy (EBRT) were enrolled on prospective IRB approved advanced imaging protocols. Patients underwent 3T multiparametric MRI (mpMRI); a subset underwent prostate specific membrane antigen (PSMA)-based PET/CT. Pathologic confirmation was obtained unless contraindicated. RESULTS: Between January 2011 and April 2021, 51 patients with BCR after brachytherapy (n = 36) or brachytherapy + EBRT (n = 15) underwent mpMRI and were included in this analysis. Of 38 patients with available dosimetry, only two had D90<90%. The prostate and seminal vesicles were a site of failure in 66.7% (n = 34) and 39.2% (n = 20), respectively. PET/CT (n = 32 patients) more often identified lesions pelvic lymph nodes (50%; n = 16) and distant metastases (18.8%; n = 6), than mpMRI. Isolated nodal disease (9.8%; n = 5) and distant metastases (n = 1) without local recurrence were uncommon. Recurrence within the prostate was located in the transition zone in 48.5%, central or midline in 45.5%, and anterior in 36.4% of patients. CONCLUSION: In this cohort of patients with BCR after LDR brachytherapy ± EBRT, the predominant recurrence pattern was local (prostate ± seminal vesicles) with frequent occurrence in the anterior prostate and transition zone. mpMRI and PSMA PET/CT provided complementary information to localize sites of recurrence, with PSMA PET/CT often confirming mpMRI findings and identifying occult nodal or distant metastases.

A Pilot Study of Dynamic 18F-DCFPyL PET/CT Imaging of Prostate Adenocarcinoma in High-Risk Primary Prostate Cancer Patients.

PURPOSE: The primary aim of this study was to investigate the pharmacokinetics of 18F-DCFPyL, an 18F-labeled PSMA-based ligand, and to explore the utility of early time point positron emission tomography (PET) imaging extracted from PET data to distinguish malignant primary prostate from benign prostate tissue. PROCEDURES: Ten consecutive patients with biopsy-proven high-risk prostate cancer underwent a dynamic 18F-DCFPyL PET/CT scan of the pelvis for the first 45 min post-injection (p.i.) followed by a static PET/CT at 2 h p.i. 18F-DCFPyL uptake values and kinetics were compared between benign prostate tissue and prostate cancer, including quantitative pharmacokinetic PET parameters extracted from 18F-DCFPyL time activity curves generated from dynamic data using a two-tissue compartment model and Patlak plots. RESULTS: 18F-DCFPyL uptake values were significantly higher in primary prostate tumors than those in benign prostatic hyperplasia (BPH) and normal prostate tissue at 5 min, 30 min, and 120 min p.i. (P = 0.0002), when examining both SUVmax and SUVmean values. The two-tissue compartment model found an overall influx value (Ki) of 0.063 in primary prostate cancer, demonstrating a Ki over 15-fold higher in malignant prostate tissue compared with BPH (Ki = 0.004) and normal prostate tissue (Ki = 0.005) (P = 0.0001). CONCLUSION: High-risk primary prostate cancer is readily identified on dynamic and static, delayed, 18F-DCFPyL PET images. The tumor-to-background ratio increases over time, with optimal 18F-DCFPyL PET/CT imaging at 120 min p.i. for evaluation of prostate cancer, but not necessarily ideal for clinical application. Primary prostate cancer demonstrates different uptake kinetics in comparison to BPH and normal prostate tissue. The 15-fold difference in Ki between prostate cancer and non-cancer (BPH and normal) tissues translates to an ability to distinguish prostate cancer from normal tissue at time points as early as 5 to 10 min p.i.

Predictors of 18F-DCFPyL PET/CT Positivity in Patients with Biochemical Recurrence of Prostate Cancer After Local Therapy.

Our objective was to investigate the factors predicting scan positivity and disease location in patients with biochemical recurrence (BCR) of prostate cancer (PCa) after primary local therapy using prostate-specific membrane antigen-targeted 18F-DCFPyL PET/CT. Methods: This was a 2-institution study including 245 BCR PCa patients after primary local therapy and negative results on conventional imaging. The patients underwent 18F-DCFPyL PET/CT. We tested for correlations of lesion detection rate and disease location with tumor characteristics, time from initial therapy, prostate-specific antigen (PSA) level, and PSA doubling time (PSAdt). Multivariate logistic regression analyses were used to determine predictors of a positive scan. Regression-based coefficients were used to develop nomograms predicting scan positivity and extrapelvic disease. Results: Overall, 79.2% (194/245) of patients had a positive 18F-DCFPyL PET/CT result, with detection rates of 48.2% (27/56), 74.3% (26/35), 84% (37/44), 96.7% (59/61), and 91.8% (45/49) for PSAs of <0.5, 0.5 to <1.0, 1.0 to <2.0, 2.0 to <5.0, and ≥5.0 ng/mL, respectively. Patients with lesions confined to the pelvis had lower PSAs than those with distant sites (1.6 ± 3.5 vs. 3.0 ± 6.3 ng/mL, P < 0.001). In patients treated with prostatectomy (n = 195), 24.1% (47/195) had a negative scan result, 46.1% (90/195) showed intrapelvic disease, and 29.7% (58/195) showed extrapelvic disease. In the postradiation subgroup (n = 50), 18F-DCFPyL PET/CT was always negative at a PSA lower than 1.0 ng/mL and extrapelvic disease was seen only when PSA was greater than 2.0 ng/mL. At multivariate analysis, PSA and PSAdt were independent predictive factors of scan positivity and the presence of extrapelvic disease in postsurgical patients, with area under the curve of 78% and 76%, respectively. PSA and PSAdt were independent predictors of the presence of extrapelvic disease in the postradiation cohort, with area under the curve of 85%. Time from treatment to scan was significantly longer for prostatectomy-bed-only recurrences than for those with bone or visceral disease (6.2 ± 6.4 vs. 2.4 ± 1.3 y, P < 0.001). Conclusion:18F-DCFPyL PET/CT offers high detection rates in BCR PCa patients. PSA and PSAdt are able to predict scan positivity and disease location. Furthermore, the presence of bone or visceral lesions is associated with shorter intervals from treatment than are prostate-bed-only recurrences. These tools might guide clinicians to select the most suitable candidates for 18F-DCFPyL PET/CT imaging.

Prognostic Features of Biochemical Recurrence of Prostate Cancer Following Radical Prostatectomy Based on Multiparametric MRI and Immunohistochemistry Analysis of MRI-guided Biopsy Specimens.

Background Although prostate MRI is routinely used for the detection and staging of localized prostate cancer, imaging-based assessment and targeted molecular sampling for risk stratification are an active area of research. Purpose To evaluate features of preoperative MRI and MRI-guided biopsy immunohistochemistry (IHC) findings associated with biochemical recurrence (BCR) of prostate cancer after surgery. Materials and Methods In this retrospective case-control study, patients underwent multiparametric MRI before MRI-guided biopsy followed by radical prostatectomy between 2008 and 2016. Lesions were retrospectively scored with the Prostate Imaging Reporting and Data System (PI-RADS) (version 2) by radiologists who were blinded to the clinical-pathologic results. The IHC staining, including stains for the ETS-related gene, phosphatase and tensin homolog, androgen receptor, prostate specific antigen, and p53, was performed with targeted biopsy specimens of the index lesion (highest suspicion at MRI and pathologic grade) and scored by pathologists who were blinded to clinical-pathologic outcomes. Cox proportional hazards regression analysis was used to evaluate associations with recurrence-free survival (RFS). Results The median RFS was 31.7 months (range, 1-101 months) for 39 patients (median age, 62 years; age range, 47-76 years) without BCR and 14.6 months (range, 1-61 months) for 40 patients (median age, 59 years; age range, 47-73 years) with BCR. MRI features that showed a significant relationship with the RFS interval included an index lesion with a PI-RADS score of 5 (hazard ratio [HR], 2.10; 95% CI: 1.05, 4.21; P = .04); index lesion burden, defined as ratio of index lesion volume to prostate volume (HR, 1.55; 95% CI: 1.2, 2.1; P = .003); and suspicion of extraprostatic extension (EPE) (HR, 2.18; 95% CI: 1.1, 4.2; P = .02). Presurgical multivariable analysis indicated that suspicion of EPE at MRI (adjusted HR, 2.19; 95% CI: 1.1, 4.3; P = .02) and p53 stain intensity (adjusted HR, 2.22; 95% CI: 1.0, 4.7; P = .04) were significantly associated with RFS. Conclusion MRI features, including Prostate Imaging Reporting and Data System score, index lesion burden, extraprostatic extension, and preoperative guided biopsy p53 immunohistochemistry stain intensity are associated with biochemical relapse of prostate cancer after surgery. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Costa in this issue.

Pilot study of gadoxetate disodium-enhanced mri for localized and metastatic prostate cancers.

OATP1B3 is expressed de novo in primary prostate cancer tissue and to a greater degree in prostate cancer metastases. Gadoxetate disodium is a substrate of OATP1B3, and its uptake has been shown to correlate with OATP1B3 expression in other cancers. We aimed to evaluate use of gadoxetate disodium to image prostate cancer and to track its utility as a biomarker. A single center open-label non-randomized pilot study recruited men with (1) localized, and (2) metastatic castration resistant prostate cancer (mCRPC). Gadoxetate disodium-enhanced MRI was performed at four timepoints post-injection. The Wilcoxon signed rank test was used to compare MRI contrast enhancement ratio (CER) pre-injection and post-injection. OATP1B3 expression was evaluated via immunohistochemistry (IHC) and a pharmacogenomic analysis of OATP1B3, NCTP and OATP1B1 was conducted. The mCRPC subgroup (n = 9) demonstrated significant enhancement compared to pre-contrast images at 20-, 40- and 60-min timepoints (p < 0.0078). The localized cancer subgroup (n = 11) demonstrated earlier enhancement compared to the mCRPC group, but no retention over time (p > 0.05). OATP1B3 expression on IHC trended higher contrast enhancement between 20-40 min (p ≤ 0.064) and was associated with contrast enhancement at 60 min (p = 0.0422). OATP1B1 haplotype, with N130D and V174A substitutions, impacted enhancement at 40-60 min (p ≤ 0.038). mCRPC lesions demonstrate enhancement after injection of gadoxetate disodium on MRI and retention over 60 min. As inter-individual variability in OATP1B3 expression and function has both predictive and prognostic significance, gadoxetate disodium has potential as a biomarker in prostate cancer.

Evaluating Biochemically Recurrent Prostate Cancer: Histologic Validation of 18F-DCFPyL PET/CT with Comparison to Multiparametric MRI.

Background Prostate cancer recurrence is found in up to 40% of men with prior definitive (total prostatectomy or whole-prostate radiation) treatment. Prostate-specific membrane antigen PET agents such as 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) may improve detection of recurrence compared with multiparametric MRI; however, histopathologic validation is lacking. Purpose To determine the sensitivity, specificity, and positive predictive value (PPV) of 18F-DCFPyL PET/CT based on histologic analysis and to compare with pelvic multiparametric MRI in men with biochemically recurrent prostate cancer. Materials and Methods Men were prospectively recruited after prostatectomy and/or radiation therapy with rising prostate-specific antigen level (median, 2.27 ng/mL; range, 0.2-27.45 ng/mL) and a negative result at conventional imaging (bone scan and/or CT). Participants underwent 18F-DCFPyL PET/CT imaging and 3.0-T pelvic multiparametric MRI. Statistical analysis included Wald and modified χ2 tests. Results A total of 323 lesions were visualized in 77 men by using 18F-DCFPyL or multiparametric MRI, with imaging detection concordance of 25% (82 of 323) when including all lesions in the MRI field of view and 53% (52 of 99) when only assessing prostate bed lesions. 18F-DCFPyL depicted more pelvic lymph nodes than did MRI (128 vs 23 nodes). Histologic validation was obtained in 80 locations with sensitivity, specificity, and PPV of 69% (25 of 36; 95% confidence interval [CI]: 51%, 88%), 91% (40 of 44; 95% CI: 74%, 98%), and 86% (25 of 29; 95% CI: 73%, 97%) for 18F-DCFPyL and 69% (24 of 35; 95% CI: 50%, 86%), 74% (31 of 42; 95% CI: 42%, 89%), and 69% (24 of 35; 95% CI: 50%, 88%) for multiparametric MRI (P = .95, P = .14, and P = .07, respectively). In the prostate bed, sensitivity, specificity, and PPV were 57% (13 of 23; 95% CI: 32%, 81%), 86% (18 of 21; 95% CI: 73%, 100%), and 81% (13 of 16; 95% CI: 59%, 100%) for 18F-DCFPyL and 83% (19 of 23; 95% CI: 59%, 100%), 52% (11 of 21; 95% CI: 29%, 74%), and 66% (19 of 29; 95% CI: 44%, 86%) for multiparametric MRI (P = .19, P = .02, and P = .17, respectively). The addition of 18F-DCFPyL to multiparametric MRI improved PPV by 38% overall (P = .02) and by 30% (P = .09) in the prostate bed. Conclusion Findings with 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) were histologically validated and demonstrated high specificity and positive predictive value. In the pelvis, 18F-DCFPyL depicted more lymph nodes and improved positive predictive value and specificity when added to multiparametric MRI. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Zukotynski and Rowe in this issue.

18F-DCFPyL PET/CT Imaging in Patients with Biochemically Recurrent Prostate Cancer After Primary Local Therapy.

Our objective was to investigate the lesion detection rate of 18F-DCFPyL PET/CT, a prostate-specific membrane antigen (PSMA)-targeted PET agent, in patients with biochemically relapsed prostate cancer after primary local therapy. Methods: This was a prospective institutional review board-approved study of 90 patients with documented biochemical recurrence (median prostate-specific antigen [PSA], 2.5 ng/mL; range, 0.21-35.5 ng/mL) and negative results on conventional imaging after primary local therapies, including radical prostatectomy (n = 38), radiation (n = 27), or a combination of the two (n = 25). Patients on androgen deprivation therapy were excluded. Patients underwent whole-body 18F-DCFPyL PET/CT (299.9 ± 15.5 MBq) at 2 h after injection. The PSMA PET lesion detection rate was correlated with PSA, PSA kinetics, and original primary tumor grade. Results: Seventy patients (77.8%) showed positive PSMA PET results, with a total of 287 lesions identified: 37 prostate bed foci, 208 lesions in lymph nodes, and 42 in distant sites in bones or organs, Eleven patients had negative results, and 9 patients showed indeterminate lesions, which were considered negative in this study. The detection rates were 47.6% (n = 10/21), 50% (n = 5/10), 88.9% (n = 8/9), and 94% (n = 47/50) for PSA levels of >0.2 to <0.5, 0.5 to <1.0, 1 to <2.0, and ≥2.0 ng/mL, respectively. In postsurgical patients, PSA, PSA doubling time, and PSA velocity correlated with PET results, but the same was not true for postradiation patients. These parameters also correlated with the extent of disease on PET (intrapelvic vs. extrapelvic). There was no significant difference in the rate of positive scans between patients with higher-grade and lower-grade primary tumors (Gleason score of ≥4 + 3 vs. <3 + 4). Tumor recurrence was histology-confirmed in 40% (28/70) of patients. On a per-patient basis, positive predictive value was 93.3% (95% confidence interval, 77.6%-99.2%) by histopathologic validation and 96.2% (95% confidence interval, 86.3%-99.7%) by the combination of histology and imaging/clinical follow-up. Conclusion:18F-DCFPyL PET/CT imaging offers high detection rates in biochemically recurrent prostate cancer patients and is positive in about 50% of patients with a PSA level of less than 0.5 ng/mL, which could substantially impact clinical management. In postsurgical patients, 18F-DCFPyL PET/CT correlates with PSA, PSA doubling time, and PSA velocity, suggesting it may have prognostic value. 18F-DCFPyL PET/CT is highly promising for localizing sites of recurrent prostate cancer.

A Prospective Comparison of 18F-Sodium Fluoride PET/CT and PSMA-Targeted 18F-DCFBC PET/CT in Metastatic Prostate Cancer.

The purpose of this study was to compare the diagnostic performance of 18F-DCFBC PET/CT, a first-generation 18F-labeled prostate-specific membrane antigen (PSMA)-targeted agent, and 18F-NaF PET/CT, a sensitive marker of osteoblastic activity, in a prospective cohort of patients with metastatic prostate cancer. Methods: Twenty-eight prostate cancer patients with metastatic disease on conventional imaging prospectively received up to 4 PET/CT scans. All patients completed baseline 18F-DCFBC PET/CT and 18F-NaF PET/CT scans, and 23 patients completed follow-up imaging, with a median follow-up interval of 5.7 mo (range, 4.2-12.6 mo). Lesion detection was compared across the 2 PET/CT agents at each time point. Detection and SUV characteristics of each PET/CT agent were compared with serum prostate-specific antigen (PSA) levels and treatment status at the time of baseline imaging using nonparametric statistical testing (Spearman correlation, Wilcoxon rank). Results: Twenty-six patients had metastatic disease detected on 18F-NaF or 18F-DCFBC at baseline, and 2 patients were negative on both scans. Three patients demonstrated soft tissue-only disease. Of 241 lesions detected at baseline, 56 were soft-tissue lesions identified by 18F-DCFBC only and 185 bone lesions detected on 18F-NaF or 18F-DCFBC. 18F-NaF detected significantly more bone lesions than 18F-DCFBC (P < 0.001). Correlation of PSA with patient-level SUV metrics was strong in 18F-DCFBC (ρ > 0.5, P < 0.01) and poor in 18F-NaF (ρ < 0.3, P > 0.1). When PSA levels were combined with treatment status, patients with below-median levels of PSA (<2 ng/mL) on androgen deprivation therapy (n = 11) demonstrated more lesions on 18F-NaF than 18F-DCFBC (P = 0.02). In PSA greater than 2 ng/mL, patients on androgen deprivation therapy (n = 8) showed equal to or more lesions on 18F-DCFBC than on 18F-NaF. Conclusion: The utility of PSMA-targeting imaging in metastatic prostate cancer appears to depend on patient disease course and treatment status. Compared with 18F-NaF PET/CT, 18F-DCFBC PET/CT detected significantly fewer bone lesions in the setting of early or metastatic castrate-sensitive disease on treatment. However, in advanced metastatic castrate-resistant prostate cancer, 18F-DCFBC PET/CT shows good concordance with NaF PET/CT.

Clinical impact of PSMA-based 18F-DCFBC PET/CT imaging in patients with biochemically recurrent prostate cancer after primary local therapy.

PURPOSE: The purpose of our study was to assess 18F-DCFBC PET/CT, a PSMA targeted PET agent, for lesion detection and clinical management of biochemical relapse in prostate cancer patients after primary treatment. METHODS: This is a prospective IRB-approved study of 68 patients with documented biochemical recurrence after primary local therapy consisting of radical prostatectomy (n = 50), post radiation therapy (n = 9) or both (n = 9), with negative conventional imaging. All 68 patients underwent whole-body 18F-DCFBC PET/CT, and 62 also underwent mpMRI within one month. Lesion detection with 18F-DCFBC was correlated with mpMRI findings and pre-scan PSA levels. The impact of 18F-DCFBC PET/CT on clinical management and treatment decisions was established after 6 months' patient clinical follow-up. RESULTS: Forty-one patients (60.3%) showed at least one positive 18F-DCFBC lesion, for a total of 79 lesions, 30 in the prostate bed, 39 in lymph nodes, and ten in distant sites. Tumor recurrence was confirmed by either biopsy (13/41 pts), serial CT/MRI (8/41) or clinical follow-up (15/41); there was no confirmation in five patients, who continue to be observed. The 18F-DCFBC and mpMRI findings were concordant in 39 lesions (49.4%), and discordant in 40 lesions (50.6%); the majority (n = 32/40) of the latter occurring because the recurrence was located outside the mpMRI field of view. 18F-DCFBC PET positivity rates correlated with PSA values and 15%, 46%, 83%, and 77% were seen in patients with PSA values <0.5, 0.5 to <1.0, 1.0 to <2.0, and ≥2.0 ng/mL, respectively. The optimal cut-off PSA value to predict a positive 18F-DCFBC scan was 0.78 ng/mL (AUC = 0.764). A change in clinical management occurred in 51.2% (21/41) of patients with a positive 18F-DCFBC result, generally characterized by starting a new treatment in 19 patients or changing the treatment plan in two patients. CONCLUSIONS: 18F-DCFBC detects recurrences in 60.3% of a population of patients with biochemical recurrence, but results are dependent on PSA levels. Above a threshold PSA value of 0.78 ng/mL, 18F-DCFBC was able to identify recurrence with high reliability. Positive 18F-DCFBC PET imaging led clinicians to change treatment strategy in 51.2% of patients.

A comparison of prostate cancer bone metastases on 18F-Sodium Fluoride and Prostate Specific Membrane Antigen (18F-PSMA) PET/CT: Discordant uptake in the same lesion.

PURPOSE: Prostate-Specific Membrane Antigen (PSMA) PET/CT has been introduced as a sensitive method for characterizing metastatic prostate cancer. The purpose of this study is to compare the spatial concordance of 18F-NaF PET/CT and 18F-PSMA-targeted PET/CT within prostate cancer bone metastases. METHODS: Prostate cancer patients with known bone metastases underwent PSMA-targeted PET/CT (18F-DCFBC or 18F-DCFPyL) and 18F-NaF PET/CT. In pelvic and spinal lesions detected by both radiotracers, regions-of-interest (ROIs) derived by various thresholds of uptake intensity were compared for spatial colocalization. Overlap volume was correlated with uptake characteristics and disease status. RESULTS: The study included 149 lesions in 19 patients. Qualitatively, lesions exhibited a heterogeneous range of spatial concordance between PSMA and NaF uptake from completely matched to completely discordant. Quantitatively, overlap volume decreased as a function of tracer intensity. and disease status, where lesions from patients with castration-sensitive disease showed higher spatial concordance while lesions from patients with castration-resistant disease demonstrated more frequent spatial discordance. CONCLUSION: As metastatic prostate cancer progresses from castration-sensitive to castration-resistant, greater discordance is observed between NaF PET and PSMA PET uptake. This may indicate a possible phenotypic shift to tumor growth that is more independent of bone remodeling via osteoblastic formation.

18F-DCFBC Prostate-Specific Membrane Antigen-Targeted PET/CT Imaging in Localized Prostate Cancer: Correlation With Multiparametric MRI and Histopathology.

PURPOSE: To assess the ability of (N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-F-fluorobenzyl-L-cysteine) (F-DCFBC), a prostate-specific membrane antigen-targeted PET agent, to detect localized prostate cancer lesions in correlation with multiparametric MRI (mpMRI) and histopathology. METHODS: This Health Insurance Portability and Accountability Act of 1996-compliant, prospective, institutional review board-approved study included 13 evaluable patients with localized prostate cancer (median age, 62.8 years [range, 51-74 years]; median prostate-specific antigen, 37.5 ng/dL [range, 3.26-216 ng/dL]). Patients underwent mpMRI and F-DCFBC PET/CT within a 3 months' window. Lesions seen on mpMRI were biopsied under transrectal ultrasound/MRI fusion-guided biopsy, or a radical prostatectomy was performed. F-DCFBC PET/CT and mpMRI were evaluated blinded and separately for tumor detection on a lesion basis. For PET image analysis, MRI and F-DCFBC PET images were fused by using software registration; imaging findings were correlated with histology, and uptake of F-DCFBC in tumors was compared with uptake in benign prostatic hyperplasia nodules and normal peripheral zone tissue using the 80% threshold SUVmax. RESULTS: A total of 25 tumor foci (mean size, 1.8 cm; median size, 1.5 cm; range, 0.6-4.7 cm) were histopathologically identified in 13 patients. Sensitivity rates of F-DCFBC PET/CT and mpMRI were 36% and 96%, respectively, for all tumors. For index lesions, the largest tumor with highest Gleason score, sensitivity rates of F-DCFBC PET/CT and mpMRI were 61.5% and 92%, respectively. The average SUVmax for primary prostate cancer was higher (5.8 ± 4.4) than that of benign prostatic hyperplasia nodules (2.1 ± 0.3) or that of normal prostate tissue (2.1 ± 0.4) at 1 hour postinjection (P = 0.0033). CONCLUSIONS: The majority of index prostate cancers are detected with F-DCFBC PET/CT, and this may be a prognostic indicator based on uptake and staging. However, for detecting prostate cancer with high sensitivity, it is important to combine prostate-specific membrane antigen PET/CT with mpMRI.

PET/CT imaging of renal cell carcinoma with (18)F-VM4-037: a phase II pilot study.

BACKGROUND: Carbonic anhydrase IX (CA-IX) is a potential imaging biomarker of clear cell renal cell carcinoma (ccRCC). Here, we report the results of a phase II clinical trial of a small molecule radiotracer targeting CA-IX ((18)F-VM4-037) in ccRCC. METHODS: Between October 2012 and May 2013, 11 patients with kidney masses underwent (18)F-VM4-037 PET/CT prior to surgery. Dynamic imaging was performed for the first 45 min post injection and whole-body imaging was obtained at 60 min post injection. Tumors were surgically excised or biopsied within 4 weeks of imaging. RESULTS: All patients tolerated the radiotracer well with no adverse events. Ten of the 11 patients had histologically confirmed malignancy. One patient had a Bosniak Type 3 cyst with no tumor found at surgery. Two patients had extrarenal disease and 9 had tumors only in the kidney. Primary ccRCC lesions were difficult to visualize on PET alone due to high uptake of the tracer in the adjacent normal kidney parenchyma, however when viewed in conjunction with CT, the tumors were easily localized. Metastatic lesions were clearly visible on PET. Mean SUV for primary kidney lesions was 2.55 in all patients; in patients with histologically confirmed ccRCC, the mean SUV was 3.16. The time-activity curves (TAC) are consistent with reversible ligand binding with peak activity concentration at 8 min post injection followed by washout. Distribution Volume Ratio (DVR) of the lesions was measured using the Logan graphical analysis method. The mean DVR value across the 9 kidney lesions was 5.2 ± 2.8, (range 0.68-10.34). CONCLUSION: 18F-VM4-037 is a well-tolerated PET agent that allows same day imaging of CA-IX expression. The agent demonstrated moderate signal uptake in primary tumors and excellent visualization of CA-IX positive metastases. While the evaluation of primary ccRCC lesions is challenging due to high background activity in the normal kidney parenchyma, 18F-VM4-037 may be most useful in the evaluation of metastatic ccRCC lesions.

Prospective Study Evaluating Na18F PET/CT in Predicting Clinical Outcomes and Survival in Advanced Prostate Cancer.

UNLABELLED: This prospective pilot study evaluated the ability of Na(18)F PET/CT to detect and monitor bone metastases over time and its correlation with clinical outcomes and survival in advanced prostate cancer. METHODS: Sixty prostate cancer patients, including 30 with and 30 without known bone metastases by conventional imaging, underwent Na(18)F PET/CT at baseline, 6 mo, and 12 mo. Positive lesions were verified on follow-up scans. Changes in SUVs and lesion number were correlated with prostate-specific antigen change, clinical impression, and overall survival. RESULTS: Significant associations included the following: SUV and prostate-specific antigen percentage change at 6 mo (P = 0.014) and 12 mo (P = 0.0005); SUV maximal percentage change from baseline and clinical impression at 6 mo (P = 0.0147) and 6-12 mo (P = 0.0053); SUV change at 6 mo and overall survival (P = 0.018); number of lesions on Na(18)F PET/CT and clinical impression at baseline (P < 0.0001), 6 mo (P = 0.0078), and 12 mo (P = 0.0029); and number of lesions on Na(18)F PET/CT per patient at baseline and overall survival (P = 0.017). In an exploratory analysis, paired (99m)Tc-methylene diphosphonate bone scans ((99m)Tc-BS) were available for 35 patients at baseline, 19 at 6 mo, and 14 at 12 mo (68 scans). Malignant lesions on Na(18)F PET/CT (n = 57) were classified on (99m)Tc-BS as malignant 65% of the time, indeterminate 25% of the time, and negative 10% of the time. Additionally, 69% of paired scans showed more lesions on Na(18)F PET/CT than on (99m)Tc-BS. CONCLUSION: The baseline number of malignant lesions and changes in SUV on follow-up Na(18)F PET/CT significantly correlate with clinical impression and overall survival. Na(18)F PET/CT detects more bone metastases earlier than (99m)Tc-BS and enhances detection of new bone disease in high-risk patients.

A Phase I Dosing Study of Ferumoxytol for MR Lymphography at 3 T in Patients With Prostate Cancer.

OBJECTIVE: The objective of our study was to determine the optimal dose of ferumoxytol for performing MR lymphography (MRL) at 3 T in patients with prostate cancer. SUBJECTS AND METHODS: This phase I trial enrolled patients undergoing radical prostatectomy (RP) with bilateral pelvic lymph node dissection (PLND). Three groups of five patients each (total of 15 patients) received IV ferumoxytol before RP with bilateral PLND at each of the following doses of iron: 4, 6, and 7.5 mg Fe/kg. Patients underwent abdominopelvic MRI at 3 T before and 24 hours after ferumoxytol injection using T2- and T2*-weighted sequences. Normalized signal intensity (SI) and normalized SD changes from baseline to 24 hours after injection within visible lymph nodes were calculated for each dose level. Linear mixed effects models were used to estimate the effects of dose on the percentage SI change and log-transformed SD change within visible lymph nodes to determine the optimal dose of ferumoxytol for achieving uniform low SI in normal nodes. RESULTS: One patient who was excluded from the study group had a mild allergic reaction requiring treatment after approximately 2.5 mg Fe/kg ferumoxytol injection whereupon the injection was interrupted. The 15 study group patients tolerated ferumoxytol at all dose levels. The mean percentage SI change in 13 patients with no evidence of lymph metastasis was -36.4%, -45.4%, and -65.1% for 4, 6, and 7.5 mg Fe/kg doses, respectively (p = 0.041). CONCLUSION: A dose level of 7.5 mg Fe/kg ferumoxytol was safe and effective in deenhancing benign lymph nodes. This dose therefore can be the starting point for future phase II studies regarding the efficacy of ferumoxytol for MRL.

Localized prostate cancer detection with 18F FACBC PET/CT: comparison with MR imaging and histopathologic analysis.

PURPOSE: To characterize uptake of 1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid ((18)F FACBC) in patients with localized prostate cancer, benign prostatic hyperplasia (BPH), and normal prostate tissue and to evaluate its potential utility in delineation of intraprostatic cancers in histopathologically confirmed localized prostate cancer in comparison with magnetic resonance (MR) imaging. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained for this HIPAA-compliant prospective study. Twenty-one men underwent dynamic and static abdominopelvic (18)F FACBC combined positron emission tomography (PET) and computed tomography (CT) and multiparametric (MP) 3-T endorectal MR imaging before robotic-assisted prostatectomy. PET/CT and MR images were coregistered by using pelvic bones as fiducial markers; this was followed by manual adjustments. Whole-mount histopathologic specimens were sliced with an MR-based patient-specific mold. (18)F FACBC PET standardized uptake values (SUVs) were compared with those at MR imaging and histopathologic analysis for lesion- and sector-based (20 sectors per patient) analysis. Positive and negative predictive values for each modality were estimated by using generalized estimating equations with logit link function and working independence correlation structure. RESULTS: (18)F FACBC tumor uptake was rapid but reversible. It peaked 3.6 minutes after injection and reached a relative plateau at 15-20 minutes (SUVmax[15-20min]). Mean prostate tumor SUVmax(15-20min) was significantly higher than that of the normal prostate (4.5 ± 0.5 vs 2.7 ± 0.5) (P < .001); however, it was not significantly different from that of BPH (4.3 ± 0.6) (P = .27). Sector-based comparison with histopathologic analysis, including all tumors, revealed sensitivity and specificity of 67% and 66%, respectively, for (18)F FACBC PET/CT and 73% and 79%, respectively, for T2-weighted MR imaging. (18)F FACBC PET/CT and MP MR imaging were used to localize dominant tumors (sensitivity of 90% for both). Combined (18)F FACBC and MR imaging yielded positive predictive value of 82% for tumor localization, which was higher than that with either modality alone (P < .001). CONCLUSION: (18)F FACBC PET/CT shows higher uptake in intraprostatic tumor foci than in normal prostate tissue; however, (18)F FACBC uptake in tumors is similar to that in BPH nodules. Thus, it is not specific for prostate cancer. Nevertheless, combined (18)F FACBC PET/CT and T2-weighted MR imaging enable more accurate localization of prostate cancer lesions than either modality alone.

Prostate cancer: can multiparametric MR imaging help identify patients who are candidates for active surveillance?

PURPOSE: To determine whether multiparametric magnetic resonance (MR) imaging can help identify patients with prostate cancer who would most appropriately be candidates for active surveillance (AS) according to current guidelines and to compare the results with those of conventional clinical assessment scoring systems, including the D'Amico, Epstein, and Cancer of the Prostate Risk Assessment (CAPRA) systems, on the basis of findings at prostatectomy. MATERIALS AND METHODS: This institutional review board-approved HIPAA-compliant retrospectively designed study included 133 patients (mean age, 59.3 years) with a mean prostate-specific antigen level of 6.73 ng/mL (median, 4.39 ng/mL) who underwent multiparametric MR imaging at 3.0 T before radical prostatectomy. Informed consent was obtained from all patients. Patients were then retrospectively classified as to whether they would have met AS eligibility criteria or were better served by surgery. AS eligibility criteria for prostatectomy specimens were a dominant tumor smaller than 0.5 mL without Gleason 4 or 5 patterns or extracapsular or seminal vesicle invasion. Conventional clinical assessment scores (the D'Amico, Epstein, and CAPRA scoring systems) were compared with multiparametric MR imaging findings for predicting AS candidates. The level of significance of difference between scoring systems was determined by using the χ(2) test for categoric variables with the level of significance set at P < .05. RESULTS: Among 133 patients, 14 were eligible for AS on the basis of prostatectomy results. The sensitivity, positive predictive value (PPV), and overall accuracy, respectively, were 93%, 25%, and 70% for the D'Amico system, 64%, 45%, and 88% for the Epstein criteria, and 93%, 20%, and 59% for the CAPRA scoring system for predicting AS candidates (P < .005 for all, χ(2) test), while multiparametric MR imaging had a sensitivity of 93%, a PPV of 57%, and an overall accuracy of 92% (P < .005). CONCLUSION: Multiparametric MR imaging provides useful additional information to existing clinicopathologic scoring systems of prostate cancer and improves the assignment of treatment (eg, AS or active treatment).

Correlation of magnetic resonance imaging tumor volume with histopathology.

PURPOSE: The biology of prostate cancer may be influenced by the index lesion. The definition of index lesion volume is important for appropriate decision making, especially for image guided focal treatment. We determined the accuracy of magnetic resonance imaging for determining index tumor volume compared with volumes derived from histopathology. MATERIALS AND METHODS: We evaluated 135 patients (mean age 59.3 years) with a mean prostate specific antigen of 6.74 ng/dl who underwent multiparametric 3T endorectal coil magnetic resonance imaging of the prostate and subsequent radical prostatectomy. Index tumor volume was determined prospectively and independently by magnetic resonance imaging and histopathology. The ellipsoid formula was applied to determine histopathology tumor volume, whereas manual tumor segmentation was used to determine magnetic resonance tumor volume. Histopathology tumor volume was correlated with age and prostate specific antigen whereas magnetic resonance tumor volume involved Pearson correlation and linear regression methods. In addition, the predictive power of magnetic resonance tumor volume, prostate specific antigen and age for estimating histopathology tumor volume (greater than 0.5 cm(3)) was assessed by ROC analysis. The same analysis was also conducted for the 1.15 shrinkage factor corrected histopathology data set. RESULTS: There was a positive correlation between histopathology tumor volume and magnetic resonance tumor volume (Pearson coefficient 0.633, p <0.0001), but a weak correlation between prostate specific antigen and histopathology tumor volume (Pearson coefficient 0.237, p = 0.003). On linear regression analysis histopathology tumor volume and magnetic resonance tumor volume were correlated (r(2) = 0.401, p <0.00001). On ROC analysis AUC values for magnetic resonance tumor volume, prostate specific antigen and age in estimating tumors larger than 0.5 cm(3) at histopathology were 0.949 (p <0.0000001), 0.685 (p = 0.001) and 0.627 (p = 0.02), respectively. Similar results were found in the analysis with shrinkage factor corrected tumor volumes at histopathology. CONCLUSIONS: Magnetic resonance imaging can accurately estimate index tumor volume as determined by histology. Magnetic resonance imaging has better accuracy in predicting histopathology tumor volume in tumors larger than 0.5 cm(3) than prostate specific antigen and age. Index tumor volume as determined by magnetic resonance imaging may be helpful in planning treatment, specifically in identifying tumor margins for image guided focal therapy and possibly selecting better active surveillance candidates.

The kinetics and reproducibility of 18F-sodium fluoride for oncology using current PET camera technology.

UNLABELLED: We evaluated the kinetics of (18)F-sodium fluoride (NaF) and reassessed the recommended dose, optimal uptake period, and reproducibility using a current-generation PET/CT scanner. METHODS: In this prospective study, 73 patients (31 patients with multiple myeloma or myeloma precursor disease and 42 with prostate cancer) were injected with a mean administered dose of 141 MBq of (18)F-NaF. Sixty patients underwent 3 sequential sessions of 3-dimensional PET/CT of the torso beginning approximately 15 min after (18)F-NaF injection, followed by whole-body 3-dimensional PET/CT at 2 h. The remaining 13 prostate cancer patients were imaged only at 2 and 3 h after injection. Twenty-one prostate cancer patients underwent repeated baseline studies (mean interval, 5.9 d) to evaluate reproducibility. RESULTS: The measured effective dose was 0.017 mSv/MBq, with the urinary bladder, osteogenic cells, and red marrow receiving the highest doses at 0.080, 0.077, and 0.028 mGy/MBq, respectively. Visual analysis showed that uptake in both normal and abnormal bone increased with time; however, the rate of increase decreased with time. A semiautomated workflow provided objective uptake parameters, including the mean standardized uptake value of all pixels within bone with SUVs greater than 10 and the average of the mean SUV of all malignant lesions identified by the algorithm. The values of these parameters for the images beginning at approximately 15 min and approximately 35 min were significantly different (0.3% change per minute). Differences between the later imaging time points were not significant (P < 0.01). Repeated baseline studies showed high intraclass correlations (>0.9) and relatively low critical percentage change (the value above which a change can be considered real) for these parameters. The tumor-to-normal bone ratio, based on the maximum SUV of identified malignant lesions, decreased with time; however, this difference was small, estimated at approximately 0.16%/min in the first hour. CONCLUSION: (18)F-NaF PET/CT images obtained with modest radiation exposures can result in highly reproducible imaging parameters. Although the tumor-to-normal bone ratio decreases slightly with time, the high temporal dependence during uptake periods less than 30 min may limit accurate quantitation. An uptake period of 60 ± 30 min has limited temporal dependence while maintaining a high tumor-to-normal bone ratio.

11C-Acetate PET/CT in localized prostate cancer: a study with MRI and histopathologic correlation.

UNLABELLED: This work characterizes the uptake of (11)C-acetate in prostate cancer (PCa), benign prostate hyperplasia, and normal prostate tissue in comparison with multiparametric MRI, whole-mount histopathology, and clinical markers to evaluate the potential utility of (11)C-acetate for delineating intraprostatic tumors in a population of patients with localized PCa. METHODS: Thirty-nine men with presumed localized PCa underwent dynamic-static abdominal-pelvic (11)C-acetate PET/CT for 30 min and 3-T multiparametric MRI before prostatectomy. PET/CT images were registered to MR images using pelvic bones for initial rotation-translation, followed by manual adjustments to account for prostate motion and deformation from the MRI endorectal coil. Whole-mount pathology specimens were sectioned using an MRI-based patient-specific mold resulting in improved registration between the MRI, PET, and pathology. (11)C-acetate PET standardized uptake values were compared with multiparametric MRI and pathology. RESULTS: (11)C-acetate uptake was rapid but reversible, peaking at 3-5 min after injection and reaching a relative plateau at approximately 10 min. The average maximum standardized uptake value (10-12 min) of tumors was significantly higher than that of normal prostate tissue (4.4 ± 2.05 [range, 1.8-9.2] vs. 2.1 ± 0.94 [range, 0.7-3.4], respectively; P < 0.001); however, it was not significantly different from that of benign prostatic hyperplasia (4.8 ± 2.01 [range, 1.8-8.8]). A sector-based comparison with histopathology, including all tumors greater than 0.5 cm, revealed a sensitivity and specificity of 61.6% and 80.0%, respectively, for (11)C-acetate PET/CT and 82.3% and 95.1%, respectively, for MRI. The (11)C-acetate accuracy was comparable to that of MRI when only tumors greater than 0.9 cm were considered. In a small cohort (n = 9), (11)C-acetate uptake was independent of fatty acid synthase expression using immunohistochemistry. CONCLUSION: (11)C-acetate PET/CT demonstrates higher uptake in tumor foci than in normal prostate tissue; however, (11)C-acetate uptake in tumors is similar to that in benign prostate hyperplasia nodules. Although (11)C-acetate PET/CT is not likely to have utility as an independent modality for evaluation of localized PCa, the high uptake in tumors may make it useful for monitoring focal therapy when tissue damage after therapy may limit anatomic imaging methods.

Multiparametric 3T prostate magnetic resonance imaging to detect cancer: histopathological correlation using prostatectomy specimens processed in customized magnetic resonance imaging based molds.

PURPOSE: We determined the prostate cancer detection rate of multiparametric magnetic resonance imaging at 3T. Precise one-to-one histopathological correlation with magnetic resonance imaging was possible using prostate magnetic resonance imaging based custom printed specimen molds after radical prostatectomy. MATERIALS AND METHODS: This institutional review board approved prospective study included 45 patients (mean age 60.2 years, range 49 to 75) with a mean prostate specific antigen of 6.37 ng/ml (range 2.3 to 23.7) who had biopsy proven prostate cancer (mean Gleason score of 6.7, range 6 to 9). Before prostatectomy all patients underwent prostate magnetic resonance imaging using endorectal and surface coils on a 3T scanner, which included triplane T2-weighted magnetic resonance imaging, apparent diffusion coefficient maps of diffusion weighted magnetic resonance imaging, dynamic contrast enhanced magnetic resonance imaging and spectroscopy. The prostate specimen was whole mount sectioned in a customized mold, allowing geometric alignment to magnetic resonance imaging. Tumors were mapped on magnetic resonance imaging and histopathology. Sensitivity, specificity, positive predictive value and negative predictive value of magnetic resonance imaging for cancer detection were calculated. In addition, the effects of tumor size and Gleason score on the sensitivity of multiparametric magnetic resonance imaging were evaluated. RESULTS: The positive predictive value of multiparametric magnetic resonance imaging to detect prostate cancer was 98%, 98% and 100% in the overall prostate, peripheral zone and central gland, respectively. The sensitivity of magnetic resonance imaging sequences was higher for tumors larger than 5 mm in diameter as well as for those with higher Gleason scores (greater than 7, p <0.05). CONCLUSIONS: Prostate magnetic resonance imaging at 3T allows for the detection of prostate cancer. A multiparametric approach increases the predictive power of magnetic resonance imaging for diagnosis. In this study accurate correlation between multiparametric magnetic resonance imaging and histopathology was obtained by the patient specific, magnetic resonance imaging based mold technique.