From the Department of Radiology, Brooke Army Medical Center, 3551 Roger Brooke Dr, San Antonio, TX 78219 (M.G., J.G.P., M.N.C., K.P.B.); Department of Radiology, 10th Medical Group, U.S. Air Force Academy, Colo (J.A.A.); Mountain Medical Physician Specialists, Salt Lake City, Utah (S.B.A.); and Uniformed Services University of the Health Sciences, Bethesda, Md (M.N.C., K.P.B.).
Fluorine 18 (18F) fluciclovine (anti-1-amino-3–18F-fluorocyclobutane-1-carboxylic acid [FACBC]) is a radiolabeled amino acid analog that takes advantage of the amino acid transport upregulation in several types of cancer cells. FACBC is taken up to a greater extent in prostate cancer cells than in surrounding normal tissue, providing an opportunity for its use in cases of this common cancer. In 2016, the U.S. Food and Drug Administration found the accuracy of FACBC PET to be superior to that of other molecular imaging techniques and subsequently granted approval for its use in PET of recurrent prostate cancer. As FACBC is an 18F radiotracer, an on-site cyclotron is not required for its production. This feature enables the widespread clinical availability of this agent and, in turn, an opportunity for improved patient care. The clinical pharmacology and imaging features of FACBC are reviewed, and the role of this agent in the imaging of recurrent prostate cancer, within the context of research that supports its effectiveness, is discussed. The administration of and image acquisition facilitated by using FACBC, as compared with 18F fluorodeoxyglucose, which is more widely used, are described. In addition, the criteria for interpreting FACBC imaging findings are outlined, with emphasis on common causes of false-positive and false-negative findings.
After completing this journal-based SA-CME activity, participants will be able to:
■ Describe the imaging and clinical pharmacology features of FACBC.
■ Discuss the relevant details of FACBC administration and the associated image acquisition in contrast to those associated with FDG, the more widely used agent.
■ List the criteria used to interpret FACBC imaging findings in the setting of suspected recurrent prostate cancer.
Prostate cancer is the second leading cause of cancer-related mortality in men (1). At least one-third of patients who undergo definitive treatment have cancer relapse (2,3). Recurrent disease is typically discovered owing to an increase in prostate-specific antigen (PSA) levels. However, the location and extent of recurrence cannot be easily or accurately assessed by means of conventional imaging, and this limitation complicates treatment management (4). There is no agreement regarding the size of the pelvic radiation field in patients with recurrent disease, and the presence of extrapelvic metastatic disease typically excludes patients from salvage radiation therapy (5,6). Therefore, identification of the extent of pelvic disease and detection of extrapelvic metastases significantly affect plans for subsequent salvage radiation therapy (7).
Fluorine 18 (18F) fluciclovine, or anti-1-amino-3–18F-fluorocyclobutane-1-carboxylic acid (FACBC), was developed to address the shortcomings of current imaging techniques. This compound takes advantage of the increased amino acid transport in prostate cancer cells. Labeling with 18F enables the widespread clinical use of FACBC. The use of FACBC was approved by the U.S. Food and Drug Administration (FDA) in May of 2016, and this agent is now available for imaging of suspected prostate cancer recurrence following treatment (3).
Physiologic Distribution of FACBC
FACBC is a radiolabeled analog of levorotatory leucine, which is an essential amino acid. Like levorotatory leucine, FACBC is taken up via the human L-type amino acid transporter and alanine-serine-cysteine transporter systems. As such, FACBC demonstrates the highest uptake in tissues that produce proteins or process amino acids. L-type amino acid transporter and alanine-serine-cysteine transporter systems are upregulated in many carcinomas, including prostate cancer, with the L-type amino acid and alanine-serine-cysteine transporter subtypes associated with more aggressive disease (8–10).
Once inside the cell, FACBC does not undergo metabolism and can transit out of the cell via the same channels through which it entered. A comparison of the different ways that different prostate imaging radiopharmaceuticals interact with prostate cancer cells is shown in Figure 1.
FACBC Imaging Characteristics
As in other publications that describe FACBC, in this review, we characterize the intensity of FACBC uptake that indicates potential malignancy by comparing this uptake with that in the blood pool, bone marrow, and liver. Avidity equal to or greater than that of the blood pool but less than that of the bone marrow is considered to be mild. Avidity equal to or greater than that of bone marrow but less than that of the liver is considered to be moderate. Avidity equal to or greater than that of the liver is considered to be intense.
The most intense physiologic tracer uptake is seen in the pancreas (Fig 2). However, this uptake decreases within 15 minutes after injection of the radiopharmaceutical such that the avidity of the pancreas decreases to a level lower than that of the liver. The liver has the second most intense physiologic activity and is the critical organ (11,12). There is moderate salivary gland and pituitary gland uptake and variable mild to moderate bowel activity (11). Two tissue types demonstrate dynamic uptake, which changes during the course of the scanning examination: Red marrow activity peaks at a moderate intensity 10–15 minutes after the injection and decreases over time. Conversely, muscle uptake is mild during the early phases of the examination and increases over time.
There is minimal to no activity in the excreted urine, and even when FACBC accumulates in the bladder, the accumulation is much milder than that of FDG, and it rarely interferes with image interpretation.
Occasionally, a patient has early bladder wall activity, which may need to be considered when the deep pelvis is evaluated. Other organs without significant uptake include the lungs and the brain, although the pituitary gland demonstrates mild to moderate activity in the majority of individuals.
Due to the rapid influx and efflux of amino acids and thus FACBC in prostate cancer, the pathologic activity in prostate tumors and nodal metastatic disease peaks rapidly, between 4 and 10 minutes, after the radiotracer injection (Fig 3).
This is in stark contrast to the pathologic activity of FDG, which peaks within 45–90 minutes in most tumors. In fact, by 90 minutes, greater than 60% of the FACBC at peak tumoral activity has washed out (12). The dynamic findings in tumor cells and muscle tissue dictate the imaging protocol. PET imaging begins 3–5 minutes after the injection of radiotracer.
Scanning from the midthigh to the skull base (caudal to cranial) optimizes the target-to–background tissue ratio by maximizing pathologic pelvic uptake while minimizing uptake in the background muscle tissue.
Before May of 2016, only two radiotracers were FDA approved for imaging in the setting of biochemical recurrence of prostate cancer: 111In–capromab pendetide was approved in 1999, and 11C-choline was approved in 2012. Given this factor, the FDA focused its review on two studies (13,14) during the process of approving the use of FACBC. In these studies, FACBC PET/CT was compared with 111In–capromab pendetide SPECT/CT at Emory University (13) and with 11C-choline PET/CT at the University of Bologna (14).
In the Emory University study (13), 93 patients suspected of having recurrent prostate cancer underwent FACBC PET/CT and 111In–capromab pendetide SPECT/CT within 90 days of each other. The images were interpreted by two blinded readers, with consensus reading performed in discordant cases. A consensus panel determined whether patients were believed to have prostate or prostatectomy bed disease. Patients with extraprostatic findings at FACBC PET/CT or 111In–capromab pendetide SPECT/CT underwent targeted biopsy. The effectiveness of FACBC imaging findings was compared with that of the histologic results. FACBC imaging had higher sensitivity, specificity, accuracy, positive predictive value, and negative predictive value in the detection of prostate, prostatectomy bed, and extraprostatic disease compared with 111In–capromab pendetide imaging (Table 1).
Table 1: Performance of FACBC and 111In–Capromab Pendetide Scanning in 93 Patients
Note.—Data are performance values for FACBC and 111In–capromab pendetide scanning in the detection of prostate, prostatectomy bed, or extraprostatic disease in 93 patients at Emory University who were suspected of having recurrent prostate cancer. NPV = negative predictive value, PPV = positive predictive value.
Compared with 111In–capromab pendetide scanning, FACBC scanning depicted 14 more prostatectomy bed tumor recurrences (55 vs 41) and enabled the identification of 18 more patients with extraprostatic involvement (22 versus four). FACBC scanning results led to correct tumor grade upgrading in 18 (26%) of 70 cases. In addition, the amount of patient radiation exposure in the FACBC examinations was approximately one-third the amount in the 111In–capromab pendetide examinations.
In the University of Bologna study (14), 50 patients suspected of having recurrent prostate cancer underwent FACBC PET/CT and 11C-choline PET/CT within 1 week of each other. The images were interpreted by two blinded readers, with consensus reading performed in discordant cases. Cancer recurrence was successfully identified with FACBC PET/CT in six patients whose 11C-choline PET results were negative. There were no patients with negative FACBC PET/CT results but positive 11C-choline scanning results. Results of the majority of the imaging examinations (n = 33) performed in the remaining patients were concurrently negative for recurrent prostate cancer.
Findings in the Emory University (Table 2) (13) and University of Bologna (14) studies demonstrated that the sensitivity of FACBC scanning increased with increasing PSA levels (15).
Table 2: Performance Values for FACBC Scanning Based on PSA Levels
Note.—Data are negative predictive value (NPV) and positive predictive value (NPV) percentages for FACBC scanning of recurrent prostate cancer, based on PSA levels, from an FDA review of data from an Emory University study.
Similarly, in the setting of recurrent prostate cancer, the diagnostic performance of FACBC PET/CT has also been shown to be superior to that of conventional CT. In one study (16), 53 men with biochemical prostate cancer recurrence and negative bone scan findings underwent FACBC PET/CT and diagnostic CT within 90 days of each other. FACBC PET/CT had a fourfold higher true-positive result rate and double the accuracy compared with CT. FACBC scanning also enabled much better delineation of recurrent prostate versus extraprostatic cancer at all PSA levels, PSA doubling times, and original Gleason scores (16).
The significance of these study findings is best illustrated by the results of the phase III FALCON (Fluciclovine [18F] PET/CT in biochemicAL reCurrence Of prostate caNcer) trial (17), in which the important effects of FACBC PET/CT on the treatment of patients with biochemical recurrence of prostate cancer were studied. In this study involving 85 patients, FACBC scan findings led to revision of the treatment plan for 52 men. Sixty percent of these cases involved major changes in the planned treatment, with salvage therapy changed to systemic therapy or watchful waiting. The other 40% of cases involved modification of the planned radiation therapy.
Since the FDA approval of FACBC use in 2016, progress has been made with another PET imaging agent, 68Ga–PSMA 11, in the imaging of prostate cancer. In a recent international study (18) involving 270 patients suspected of having prostate cancer recurrence following radical prostatectomy, PSMA 11 facilitated the identification of 132 patients with positive imaging findings. This population included only those patients whose PSA levels were lower than 1 ng/mL. This is notable because FACBC PET is less likely to yield positive results in patients with PSA levels lower than 1 ng/mL, unless the doubling time is rapid.
However, there are limited data on the direct comparison of FACBC with PSMA 11. Calais et al (19) performed a retrospective head-to-head comparison of these two agents. Their study involved 10 patients who were enrolled in a PSMA 11 trial and had previously undergone FACBC PET/CT within 0.2–4.2 months (mean, 2.3 months) of subsequent PSMA 11 imaging. The PSMA 11 examination appeared to be more sensitive in this group, with positive PSMA 11 scan findings and discordantly negative FACBC scan findings in five (50%) of the 10 patients. In an additional two (20%) of the 10 patients, both examinations had positive findings; however, the PSMA 11 scans showed additional sites of disease.
The Calais et al study (19) was limited in that only one patient had histologic confirmation, the median 2.6-month interval between the FACBC and PSMA 11 examinations favored lesion detection with PSMA 11 scanning, and there was bias in the selection of patients who underwent FACBC PET/CT and subsequent PSMA 11 imaging.
To help decrease their muscle uptake, patients are instructed to avoid strenuous exercise the day before they are scheduled to undergo FACBC scanning. Patients are also asked to fast for at least 4 hours before the imaging examination to decrease their levels of circulating amino acids that may compete with FACBC for uptake (20). In addition, they are instructed to not void for 30 minutes before the FACBC injection. This instruction is based on the expert opinion that a full bladder may decrease the amount of FACBC that is excreted into the bladder and/or cause the dilution of any excreted radiotracer (21).
Radiotracer Injection and Image Acquisition
The radiotracer is injected with the patient placed supine on the PET/CT scanning bed. Following the injection, the arms are repositioned above the head and CT scanning is initiated. This usually facilitates the initiation of PET scan acquisition 3–5 minutes (target, 4 minutes) following the injection. We instruct our technologists to pause if less than 3 minutes have passed, as increased blood pool activity may be encountered if scanning is started too early.
Scanning is initiated at the upper thigh and proceeds cranially to the base of the skull, with a total imaging time of approximately 20–30 minutes. This allows for an approximately 5-minute image acquisition time in the pelvic bed position, with 3–5 minutes per bed position cranial to the pelvis. However, these times should be optimized for specific equipment (21). Figure 4 summarizes a typical FACBC scanning protocol.
This protocol is in stark contrast to that for FDG PET, in which blood glucose levels are monitored immediately before the injection, scans are obtained after an uptake period of 45–90 minutes, and patients are instructed to void immediately before the scanning examination (Table 3).
Table 3: Important Differences between FACBC PET and FDG PET Imaging Protocols
Image Interpretation Criteria
FACBC uptake is assessed visually rather than by relying on SUVs. Pathologic lesion uptake, as compared with the uptake in surrounding normal structures, should be focal and stand out visually. Soft-tissue sites of avidity for which the anatomic correlate is 1 cm or larger are considered abnormal if the avidity is greater than or equal to that of bone marrow. Currently, the uptake in the L3 vertebral body is used as a standardized reference value for bone marrow avidity. For focal uptake for which the anatomic correlate is smaller than 1 cm, uptake in the blood pool is used as the internal reference (Table 4).
Table 4: Image Interpretation Criteria Based on Anatomic Location
Note.—MIP = maximum intensity projection, NaF = sodium fluoride.
*Mixed refers to bone lesions that have both lytic and sclerotic components.
The FACBC uptake pattern and associated findings at CT or other correlative imaging modalities are usually the most helpful for identifying malignant lesions. However, SUV measurements may be helpful at sites that are questionable in terms of the presence of prostate cancer recurrence according to comparisons between the SUV of the site and the reference SUV of the nontarget background tissue (eg, L3 vertebra for bone marrow). If the maximal SUV for the lesion in question exceeds the mean SUV for the L3 vertebral body by at least 20%, there is cause for concern for recurrent disease (22).
Prostate and Prostatectomy Bed
In patients who have undergone prostatectomy, focal lesions with avidity greater than or equal to that of bone marrow are suspicious for cancer (Fig 5). However, if a focus of avidity is small (<1 cm), then it must be compared with the avidity of the blood pool (Fig 6). Subcentimeter foci of avidity are considered suspicious only if their avidity significantly exceeds that of the blood pool. It should be noted that in the manufacturer’s prescribing information (12), review of only coronal PET images is recommended for aiding in the interpretation of prostate and prostatectomy bed findings.
In patients who have not undergone prostatectomy, focal asymmetric (Fig 7) or multifocal heterogeneous (Fig 8) avidity that is greater than or equal to that of bone marrow is suspicious for tumor recurrence. Diffuse homogeneous prostate gland avidity should be suspected for recurrent cancer if it is much greater than the avidity of bone marrow. However, a homogeneous uptake pattern in the prostate gland is atypical for recurrence, and other entities that can result in FACBC uptake, such as benign prostatic hypertrophy, prostatitis, and postradiation inflammation, also should be considered (Fig 9). As such, higher false-positive rates are seen in patients with an intact prostate.
Subcentimeter foci of uptake are considered to be suspicious for recurrence only if they are significantly more avid than the blood pool. It should be noted that there have been anecdotal reports of focal median lobe uptake with a high likelihood of being false positive for recurrence; thus, this uptake finding should be viewed with a degree of skepticism.
When evaluating lymph nodes, one must consider whether their uptake features are typical or atypical of prostate cancer recurrence. The typical sites of nodal recurrence are the pelvic and retroperitoneal regions, including para-aortic, common iliac, internal iliac, and proximal external iliac nodal regions. When assessing focal uptake that corresponds to an enlarged lymph node in a typical site of prostate cancer spread, avidity greater than or equal to that of bone marrow is considered to be suspicious (Fig 10). The absence of such uptake favors a lymph node that is free of disease (Fig 11). As in the evaluation for possible prostate or prostatectomy bed recurrence, when evaluating lymph nodes for possible recurrence, subcentimeter nodes should be considered suspicious when their FACBC uptake significantly exceeds that of the blood pool (Fig 12).
Atypical sites of nodal spread include the inguinal, distal external iliac, hilar, and axillary regions. Mild symmetric uptake in these nodes typically is physiologic (Fig 13). However, if uptake is present in the setting of other, clearly malignant disease (Fig 14) or it cannot be explained by the clinical history and/or an adjacent pathologic process (eg, vascular graft placement, arthroplasty), then it may be considered suspicious for prostate cancer recurrence. The caveat to this is that FACBC can be taken up by nonprostate cancer cells, as other carcinomas also upregulate amino acid transport. Breast and colon cancers are frequently implicated mimics of prostate cancer, and lymphoma is an occasional mimic. Therefore, if a cluster of FACBC-avid lymph nodes with a distribution resembling that of another cancer is encountered, then the images should be scrutinized for evidence of a second primary cancer.
Focal osseous uptake that is clearly visualized on MIP or PET images can be considered suspicious for cancer (Fig 15). Lytic bone metastases typically show intense FACBC avidity. Mixed (lytic and sclerotic) bone lesions most commonly show moderate uptake. Even in the absence of FACBC uptake, if a densely sclerotic osseous abnormality with morphology that raises concern is visualized at CT, then metastasis must be considered. However,
densely sclerotic metastatic lesions may have no FACBC uptake.
Further evaluation can be performed with alternative imaging modalities such as MRI, 18F–sodium fluoride PET/CT, and technetium 99m–medronate SPECT/CT.
Although degenerative disk and facet uptake of FACBC is sometimes seen, it is less common and less intense than FDG uptake. Therefore, focal intense uptake for which the anatomic correlate suggests degenerative disease should be carefully assessed and considered within the context of degenerative versus malignant skeletal uptake elsewhere (Fig 16). Mild FACBC uptake in the appendicular skeleton is less worrisome, especially if there is a convincing CT correlate consistent with osteoarthritis, but it is less common and less intense compared with the uptake of FDG usually seen in this condition. Occasionally, a nonprostate malignancy such as multiple myeloma or a metastatic lesion from a second primary cancer is detected.
Intense but benign activity within a joint or at a muscular insertion also has been observed occasionally. Increased muscle uptake of FACBC is often seen following exercise (Fig 17).
In contrast to the renal excretion of FDG, there is minimal renal excretion of FACBC at the time of scanning. This may be due to the recommended protocol of imaging at 3–5 minutes after the injection in contrast to imaging at 60 minutes after the injection of FDG or other PSMA tracers. Therefore, the kidneys have no significant avidity on scans of normal findings. If renal masses are present, then any focal uptake associated with these lesions should be considered suspicious for malignancy. Schuster et al (23) studied the FACBC PET findings in a small number of patients who had clear cell (n = 4) or papillary (n = 2) renal cell carcinoma that was subsequently determined at histologic analysis. They noted the FACBC uptake in the papillary lesions to be increased relative to that in the renal parenchyma and the uptake in the clear cell lesions to be equal to or less than that in the renal parenchyma (23).
In another study, Schuster et al (11) noted that 10%–15% of patients had unilateral or bilateral adrenal uptake, even when there was no apparent anatomic correlate. Adrenal adenomas may demonstrate mildly to moderately increased FACBC avidity (Fig 18). CT images and comparison studies are helpful for characterizing these lesions as benign adrenal tumors rather than adrenal metastases, which typically demonstrate intense uptake (Fig 19).
Primary brain tumors and brain metastases have variable FACBC uptake that is usually greater than that in the brain parenchyma, which has less uptake than the blood pool. Gliomas and meningiomas with FACBC uptake have been described (Fig 20). The normal pituitary gland demonstrates moderate FACBC uptake in the majority of patients (Fig 21); however, uptake in pituitary adenomas also has been reported (Fig 22) (11). Some investigators have also reported mild uptake in the choroid plexus (24).
Infection and Inflammation
Infectious and inflammatory processes may result in increased FACBC uptake. The data on this subject are still fairly anecdotal. We have seen cases in which pneumonia caused moderately intense FACBC uptake (Fig 23). Amzat et al (25) characterized their experience with two inflammatory pulmonary lesions, which had FACBC SUVs that were lower than those of several neoplastic lesions (n = 9) but higher than the SUV of a single pulmonary carcinoid tumor.
Moderate to intense FACBC uptake in inflammatory skin lesions and in sites of infection such as those with ringworm has been reported. In addition, we frequently see mild to moderate uptake at sites of subcutaneous injections (Fig 24).
Schuster et al (11) reviewed the FACBC scans obtained in 598 subjects and noted mild to moderate linear esophageal uptake (Fig 25) in more than 50% of these subjects. The uptake tended to be most prominent in the distal esophagus and mimicked that seen with inflammatory reflux at FDG PET. Although FACBC uptake was not formally correlated with reflux esophagitis, the cause of this uptake was presumed to be based on the established relationship at FDG PET.
Anatomic variants are most relevant in the head and neck. The salivary glands demonstrate moderate FACBC uptake, and accessory parotid glands are seen in up to 15% of the general population (Fig 26), with an additional 30%–35% of the general population demonstrating a prominent anterior facial process of the parotid gland (at CT) (26). These processes typically are seen lateral to the masseter muscle and anterior to the bulk of the parotid gland. Thyroid tissue demonstrates only mild activity (11). The lymphoid tissue in the Waldeyer throat ring also demonstrates moderate uptake, which may be prominent in some patients (11). Although it has not been specifically reported, we believe that it is possible for lingual thyroid tissue to demonstrate similar uptake.
Primary Prostate Cancer Staging
Given the imaging characteristics of FACBC, there is reason to explore its use in the primary staging of prostate cancer. It seems that prostate MRI outperforms FACBC PET/CT in the characterization of prostate lesions (27). However, CT and MRI are not sufficiently sensitive in the detection of nodal disease (28). FACBC stands out in the characterization of invasive prostate disease and detection of early or distant nodal disease at the time of the diagnosis (Figs 27, 28). These features drive treatment change by enabling clinicians to define targets for surgical and radiation therapy (29). We expect future studies to help clinicians better characterize the magnitude of associated survival benefits of such treatment plan changes.
Imaging of Other Cancers
Many 18F-labeled amino acid analogs are being studied for possible use in PET of a variety of neoplasms (23,30,31). The most promising work has been in the field of breast cancer (30,32). In a study involving 27 women with locally advanced invasive ductal or invasive lobular carcinomas (33), FACBC PET/CT depicted local disease, biopsy-proven axillary nodal metastases, and even two previously unsuspected internal mammary nodes.
FACBC is the only 18F-based radiotracer that the FDA has approved for molecular imaging in patients suspected of having recurrent prostate cancer. The sensitivity of this radiotracer for the detection of recurrent and metastatic disease is higher than that of other nuclear medicine and CT agents. Physician and technologist familiarity with the FACBC imaging protocol is essential to the successful integration of this examination into existing FDG PET/CT techniques. In addition, having well-rounded knowledge of the common patterns of prostate cancer recurrence and a proper awareness of the associated image interpretation criteria is critical to maximizing the use of this new molecular imaging tool.
The authors are grateful to Erica L. Vasquez of the Brooke Army Medical Center Electronic Multimedia Image Center for creating the illustrations in Figures 1 and 4.
Recipient of a Certificate of Merit award at the 2017 RSNA Annual Meeting.
For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relationships.
The views expressed are those of the authors and do not reflect the official views or policies of the Department of Defense or its components.
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Received: Apr 6 2018 Revision requested: May 30 2018 Revision received: June 23 2018 Accepted: July 13 2018 Published online: May 06 2019 Published in print: May 2019