fluciclovine ((18)F)

Objective(s):

We performed a phase IIa clinical trial of trans-1-amino-3-18F-fluoro-cyclobutane carboxylic acid (anti-18F-FACBC), a synthetic amino acid analog for PET, in patients with metastatic prostate cancer.

Subjects

Ten male patients with prostate cancer aged 69.9 ± 7.9 years (mean ± SD) were enrolled in this study between November 2010 and March 2011 (). The inclusion criteria were: a) histological positivity for prostate cancer on two or more cores obtained by needle biopsy of the prostate; and b) presence of lymph node metastasis and/or bone metastasis demonstrated on conventional imaging such as computed tomography (CT), magnetic resonance (MR) imaging, and bone scintigraphy. Patients, who had undergone therapy for prostate cancer, including surgical resection, radiation therapy, hormonal therapy, and chemotherapy, were excluded. All patients underwent anti-18F-FACBC PET after an interval of more than 3 weeks after biopsy to avoid possible effects of biopsy on PET images. The study was performed after approval by the institutional review boards of the host institution and according to Good Clinical Practice (GCP Ordinance No. 28, 27, March 1997). Written informed consent was obtained from all patients before participation. This clinical trial was registered as JapicCTI-101326.

PET/CT Procedures

Anti-18F-FACBC was injected after fasting for 4 h or longer, followed by PET/CT imaging using a TruePoint Biograph 6 PET/CT scanner (Siemens Medical Solutions, Hoffman Estates, IL). For CT, 5 mm thick contiguous slices were acquired without the administration of contrast medium. The initial five patients underwent whole-body PET imaging (whole-body group), and the injected dose ranged from 93.8 to 287.8 MBq. Whole-body PET imaging was performed 5 min (early) and 30 min (late) after injection. Data were acquired from the mid-thigh level to the top of the head for 2.5 min per bed position. The remaining five subjects underwent 60 min dynamic PET imaging of the pelvic region immediately after injection (dynamic group), and the injected dose was fixed at approximately 200 MBq (194.3–202.4 MBq). Images for visual evaluation were reconstructed using data of 2.5 min duration and centered at 5, 15, 30, and 58 min after injection. Additionally, images were reconstructed at 15 s/frame × 4, 30 s/frame × 4, 2 min/frame × 6, 3 min/frame × 5, and 5 min/frame × 6 to assess the time course quantitatively.

Safety Assessment

The following assessments were performed before and 24 h after injection to determine the safety of a single injection of anti-18F-FACBC: interview of subjective symptoms, physical examinations, 12 lead electrocardiography, measurements of blood pressure and pulse rate, hematology, blood chemistry, and urinalysis. An interview of subjective symptoms and physical examinations were also performed at the completion of PET/CT imaging.

Discussion

The phase I clinical trial of anti-18F-FACBC in Japan indicated its safety in six young adults (). In the present phase IIa clinical trial, safety was tested in 10 patients with metastatic prostate cancer. Mild adverse events were noted in two patients, however, they resolved spontaneously without treatment, suggesting the safety of a single intravenous injection of anti-18F-FACBC in patients with prostate cancer. PET images of diagnostic quality were acquired after injection of anti-18F-FACBC ranging from 93.8 to 287.8 MBq in dose. Avidity of anti-18F-FACBC to primary prostate lesions, metastatic lymph nodes, and metastatic bone lesions was indicated. The study population was small, predominantly included patients with high Gleason scores, and did not include control subjects. Despite these limitations, the results of the present study, in combination with those of previous studies (-), warrant further investigation of diagnostic performance of anti-18F-FACBC PET in comparison with conventional imaging.

Abstract

Background. In this retrospective analysis we assessed the role of [18F]-FACBC-PET/CT in the prostatic cancer staging. Procedure. 30 first [18F]-FACBC-PET/CT images of 26 patients (68.1 ± 5.8 years) were analyzed. PET/CT findings were compared with PSA concentrations, with PSA doubling times (PDT), and with correlative imaging. Results. On 16 [18F]-FACBC (53.3%) scans, 58 metabolically active lesions were found. 12 (20.7%) lesions corresponding to the local relapse were found in prostate/prostate bed and seminal vesicles, 9 (15.5%) lesions were located in regional lymph nodes, 10 (17.2%) were located in distal lymph nodes, and 26 (44.8%) metabolically active lesions were found in the skeleton. In one case, focal uptake was found in the brain, confirmed further on MRI as meningioma. The mean S-PSA level in patients with positive [18F]-FACBC findings was 9.5 ± 16.9 μg/L (0.54–69 μg/L) and in patients with negative [18F]-FACBC findings was 1.96 ± 1.87 μg/L (0.11–5.9 μg/L), but the difference was not statistically significant. However, the PSA doubling time (PDT) in patients with positive findings was significantly shorter than PDT in patients with negative findings: 3.25 ± 2.09 months (0.3–6 months) versus 31.2 ± 22.02 months (8–84 months), P < 0.0001. There was a strong positive correlation between PSA value and number of metabolically active lesions (R = 0.74) and a negative correlation between PDT and number of metabolically active lesions (R = −0.56). There was a weak negative correlation between PDT and SUVmax⁡ (R = −0.30). Conclusion. According to our preliminary clinical experience, [18F]-FACBC-PET may play a role in in vivo restaging of an active prostate cancer, especially in patients with a short S-PSA doubling time.

2.1. Patients

30 [18F]-FACBC-PET/CT scans of 26 patients (25 with confirmed prostatic cancer in the period 1999–2013) were analyzed: age ranging from 56 to 77 years (mean age 68.1 ± 5.8); Gleason score 5–9 (mean 7.1 ± 1.4); PSA value 0.11–69 μg/L (mean 7.9 ± 14.6). FACBC-PET/CT scans for restaging were done in 25 patients with confirmed prostatic cancer and in one patient with suspicion of prostate cancer.

2.2. Imaging PET/CT Protocol

Examination was done on Siemens Biograph PET Scanner, combined with low-dose CT. The injected activity dose of [18F]-anti-FACBC ranged from 230 to 320 MBq (mean 328 ± 56.8). Early imaging was performed by starting at 8.0 ± 3.0 min (range of 4–16 min) from pelvic region using 3 min per bed position imaging protocol followed by whole body imaging from the calvarium to the midthighs at 23.4 ± 6.3 min (range of 16–37 min) using 3 min per bed position. The tracer was purchased from Uppsala (Uppsala Imanet, Sweden), and the production has been described by Sörensen et al. [].

3. Results

On 16 [18F]-FACBC-PET scans (53.3%), a total of 58 metabolic active lesions were detected. In prostate, prostate bed and seminal vesicles focal uptake was found in 12 cases (20.7%), with SUVmax⁡ ranging from 3.7 to 7.2 (mean 5.07 ± 1.9). In local lymph nodes, 9 lesions (15.5%) were found with SUVmax⁡ 4.1–10.7 (mean 8.1 ± 2.6) and, in distal lymph nodes, 10 lesions (17.2%) with SUVmax⁡ 3.4–11.9 (mean 7.35 ± 2.7) were found. A total of 26 bone lesions (44.8%) with SUVmax⁡ 4.2–8.8 (mean 5.4 ± 0.7) were observed. In one case, there was increased tracer uptake in the brain with a SUVmax⁡ 8.1 (1.7%) confirmed later on MRI as meningioma. The findings are presented for each patient individually in .

Abstract

18F-fluciclovine (trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid) is an amino acid positron emission tomography (PET) tracer used for cancer staging (e.g., prostate and breast). Patients scheduled to undergo amino acid-PET are usually required to fast before PET tracer administration. However, there have been no reports addressing whether fasting improves fluciclovine-PET imaging. In this study, the authors investigated the influence of fasting on fluciclovine-PET using triple-tracer autoradiography with 14C-fluciclovine, [5,6-3H]-2-fluoro-2-deoxy-d-glucose (3H-FDG), and 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) in a rat breast cancer model of mixed osteolytic/osteoblastic bone metastases in which the animals fasted overnight. Lesion accumulation of each tracer was evaluated using the target-to-background (muscle) ratio. The mean ratios of 14C-fluciclovine in osteolytic lesions were 4.6 ± 0.8 and 2.8 ± 0.6, respectively, with and without fasting, while those for 3H-FDG were 6.9 ± 2.5 and 5.1 ± 2.0, respectively. In the peri-tumor bone formation regions (osteoblastic), where 99mTc-HMDP accumulated, the ratios of 14C-fluciclovine were 4.3 ± 1.4 and 2.4 ± 0.7, respectively, and those of 3H-FDG were 6.2 ± 3.8 and 3.3 ± 2.2, respectively, with and without fasting. These results suggest that fasting before 18F-fluciclovine-PET improves the contrast between osteolytic and osteoblastic bone metastatic lesions and background, as well as 18F-FDG-PET.

5. Conclusions

Our findings suggest that fasting influences the uptake of 18F-fluciclovine in osteolytic and osteoblastic bone metastasis lesions, and can facilitate clearer visualization of lesions in fluciclovine-PET imaging. However, because AA metabolism is a complex process, further animal and clinical studies are required to confirm our findings.

Methods

Twenty-seven patients with recurrent or progressive primary brain tumor (based on clinical and MRI/CT data) were studied using dynamic 18F-Fluciclovine brain imaging for up to 4 h. Of these, 16 patients also had 11C-Methionine brain scans. Visual findings, semi-quantitative analyses and pharmacokinetic modeling of a subset of the 18F-Fluciclovine images was conducted. The information derived from these analyses were compared to data from 11C-Methionine and to contrast-enhanced MRI.

Results

18F-Fluciclovine was positive for all 27 patients, whereas contrast MRI was indeterminate for three patients. Tumor 18F-Fluciclovine SUVmax ranged from 1.5 to 10.5 (average: 4.5 ± 2.3), while 11C-Methionine’s tumor SUVmax ranged from 2.2 to 10.2 (average: 5.0 ± 2.2). Image contrast was higher with 18F-Fluciclovine compared to 11C-Methionine (p < 0.0001). This was due to 18F-Fluciclovine’s lower background in normal brain tissue (0.5 ± 0.2 compared to 1.3 ± 0.4 for 11C-Methionine). 18F-Fluciclovine uptake in both normal brain and tumors was well described by a simple one-compartment (three-parameter: Vb,k1,k2) model. Normal brain was found to approach transient equilibrium with a half-time that varied greatly, ranging from 1.5 to 8.3 h (mean 2.7 ± 2.3 h), and achieving a consistent final distribution volume averaging 1.4 ± 0.2 ml/cc. Tumors equilibrated more rapidly (t1/2ranging from 4 to 148 min, average 57 ± 51 min), with an average distribution volume of 3.2 ± 1.1 ml/cc. A qualitative comparison showed that the rate of normal brain uptake of 11C-Methionine was much faster than that of 18F-Fluciclovine.

Conclusion

Tumor uptake of 18F-Fluciclovine correlated well with the established brain tumor imaging agent 11C-Methionine but provided significantly higher image contrast. 18F-Fluciclovine may be particularly useful when the contrast MRI is non-diagnostic. Based on the data gathered, we were unable to determine whether Fluciclovine uptake was due solely to recurrent tumor or if inflammation or other processes also contributed.

Patients

This prospective clinical study was performed after Institutional Review Board approval (Memorial Sloan-Kettering Cancer Center IRB#03–028). Twenty-seven patients who underwent 18F-Fluciclovine brain PET for suspicion of recurrent or progressive gliomas between August 2004 and January 2008 were recruited under two different protocols (16 in the first, 11 in the second) with different funding sources (NCI and an internal source). The inclusion criteria, however, were identical and the data acquisition procedures were very similar with the primary difference being that the 11C-methionine study was left off of the second protocol. All patients fasted for at least 4 h before PET imaging. Written informed consent was obtained from all patients.

Synthesis of 18F-Fluciclovine and 11C-methionine

Clinical-grade 18F-labeled Fluciclovine and 11C-labeled methionine were produced by the Radiochemistry and Molecular Imaging Probes Core at MSKCC.

18F-Fluciclovine and 11C-methionine PET image acquisition

Following a 1-min IV infusion of 370 MBq of 18F-Fluciclovine, dynamic images of the brain were acquired in 2D mode (i.e. with septa) for 45 min on a GE Advance PET (first 21 patients) or a GE Discovery STE PET/CT (last 6 patients) scanner. The patients were subsequently removed from the scanner but returned up to three times for 20-min static images of the brain between 90 and 240 min post injection. No adverse effects were reported following the injection of 18F- Fluciclovine.

Abstract

Background: to explore the diagnostic accuracy of 18F-Fluciclovine positron-emission tomography (PET) in prostate cancer (PCa), considering both primary staging prior to radical therapy, biochemical recurrence, and advanced setting. Methods: A systematic web search through Embase and Medline was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies performed from 2011 to 2020 were evaluated. The terms used were “PET” or “positron emission tomography” or “positron emission tomography/computed tomography” or “PET/CT” or “positron emission tomography-computed tomography” or “PET-CT” and “Fluciclovine” or “FACBC” and “prostatic neoplasms” or “prostate cancer” or “prostate carcinoma”. Only studies reporting about true positive (TP), true negative (TN), false positive (FP) and false negative (FN) findings of 18F-fluciclovine PET were considered eligible. Results: Fifteen out of 283 studies, and 697 patients, were included in the final analysis. The pooled sensitivity for 18F-Fluciclovine PET/CT for diagnosis of primary PCa was 0.83 (95% CI: 0.80–0.86), the specificity of 0.77 (95% CI: 0.74–0.80). The pooled sensitivity for preoperative LN staging was 0.57 (95% CI: 0.39–0.73) and specificity of 0.99 (95% CI: 0.94–1.00). The pooled sensitivity for the overall detection of recurrence in relapsed patients was 0.68 (95% CI: 0.63–0.73), and specificity of 0.68 (95% CI: 0.60–0.75). Conclusion: This meta-analysis showed promising results in term of sensitivity and specificity for 18F-Fluciclovine PET/CT to stage the primary lesion and in the assessment of nodal metastases, and for the detection of PCa locations in the recurrent setting. However, the limited number of studies and the broad heterogeneity in the selected cohorts and in different investigation protocols are limitation affecting the strength of these results.

2. Materials and Methods

A systematic web search through Embase and Medline was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies performed from 2011 to 2020 were evaluated. The terms used were “PET” or “positron emission tomography” or “positron emission tomography/computed tomography” or “PET/CT” or “positron emission tomography-computed tomography” or “PET-CT” and “Fluciclovine” or “FACBC” and “prostatic neoplasms” or “prostate cancer” or “prostate carcinoma”. Full-text publications in English were considered. The study population comprised male patients with histologically proven PCa. Studies using 18F-Fluciclovine in pre-surgery setting as well as biochemical recurrence and advanced setting were considered. Two investigators (C.C. and C.R.) independently performed the literature search. The inclusion criteria considered for each study included an assessment of true positive (TP), true negative (TN), false positive (FP), and false negative (FN) results of 18F-Fluciclovine PET or PET / CT for the diagnosis of primary cancer, lymph node staging and the detection of recurrence. Only studies providing these information were finally included in the study. The overall quality of the studies included was independently assessed by two authors, based on the 15 modified items Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2, ) []. Discrepancies between researchers were resolved with consensus.

3.2.1. Detection of Primary Prostate Cancer Lesion

The per-patient pooled sensitivity for 18F-Fluciclovine PET/CT for the diagnosis of primary PCa was 0.83 (95% CI: 0.80–0.86), with I-square: 89.6% (a) and a pooled of specificity of 0.77 (95% CI: 0.74–0.80) with I –square: 94.8% (b). The likelihood ratio (LR) syntheses gave an overall LR+ of 5.22 (95% CI: 2.15–12.67) (c) and LR– of 0.17 (95% CI: 0.8–0.38) (d). The pooled DOR was 35.43 (95%CI: 6.66–188.55) (e). The SROC curve indicates that the area under the cure was: 0.9224 (f).