FACBC (Fluciclovine)

10.4.1 Uptake Mechanism

The uptake of [¹⁸F]Fluciclovine is mediated by sodium-dependent (Na+) and independent (Na-) amino acid transport systems [236–238]. Since [¹⁸F]Fluciclovine is not a substrate for intracellular metabolism, rapid efflux via the same transporters contribute to clearance of tracer to equilibrate intracellular amino acid pools [239]. In recurrent and castration-resistant prostate cancer both Na⁺ and Na- transport systems continue to contribute to [¹⁸F]Fluciclovine uptake while androgen receptor-mediated expression of amino acid transporters have been observed over the course of the disease [240–242].

10.4.2 Indications

Restaging

[¹⁸F]Fluciclovine PET sensitivity for detecting recurrent disease increases with higher Gleason scores, higher PSA levels, and possibly shorter PSA doubling times [243,244]. In patients with an intact prostate, [¹⁸F]Fluciclovine PET demonstrates high sensitivity and low specificity in identifying local recurrent disease with a sensitivity of 88%-90% and specificity of 32%-40% [245,246]. Thus, histological confirmation is recommended for [¹⁸F]Fluciclovine uptake in the intact prostate gland.

In recurrent extra prostatic nodal disease, [¹⁸F]Fluciclovine demonstrates high specificity and mid-to-high sensitivity depending on PSA level. The overall sensitivity, specificity, and accuracy of [¹⁸F]Fluciclovine in the detection of recurrent extra prostatic disease are 55%, 97%, and 73%, respectively [246]. A large multisite study of 596 patients similarly found a high positive predictive value (PPV) of 92.3% in the detection of extra prostatic disease [245]. In patients with PSA values of <1 ng/mL, [¹⁸F]Fluciclovine has relatively low sensitivity for extra prostatic disease ranging from 21%-39% [245]. In patients with PSA:  from 0.8 to 2.03 ng/ml sensitivity is overall approximately 60% (45% for extra prostatic recurrence); from 2.04 to 6 ng/ml it is approximately  75% (approximately 45% for extra prostatic disease); higher than 6 it is approximately 85% (approximately 60% for extra prostatic disease) [245].

If Gleason Score (GS) is analysed, the whole-body positivity doesn’t change between GS lower or equal to 6, 7, 8 or higher or equal to 9. However, for lower GS the detection rate is higher for prostate bed relapse as compared to extra prostatic areas (approximately 60% vs approximately 25%) while this ratio is opposite for high GS (approximately 20% vs 60%).

Detection of prostate cancer bone lesions

[¹⁸F]Fluciclovine has been shown to accumulate in osteolytic and osteosclerotic lesions that have a high cellular density [247]. [¹⁸F]Fluciclovine typically demonstrates intense focal uptake in lytic prostate metastatic osseous lesions, and variable activity in sclerotic lesions. Metastatic bone lesions may on [¹⁸F]Fluciclovine PET be seen prior to changes on CT. Because there may be mild to no [¹⁸F]Fluciclovine  uptake in dense sclerotic lesions, supplemental skeletal specific imaging is recommended for those patients with suspicious sclerotic lesions on CT without [¹⁸F]Fluciclovine activity [248].

Change in radiation therapy (RT) treatment and target volume definition

Conventional imaging such as CT and MRI are routinely used for the clinical target volume definition. With the introduction of functional imaging such as [¹⁸F]Fluciclovine PET/CT, more patients present with suspected extra prostatic disease [249]. A recent study reported a significant change in radiation planning in 40.5% (17/42) of patients with biochemical failure randomized to undergo [¹⁸F]Fluciclovine PET/CT in addition to standard-of-care images prior to radiation therapy [243]. In 2/17 patients, radiation therapy was cancelled due to evidence of extra pelvic disease. In 15/17 patients the pre-planning radiotherapy field was changed after [¹⁸F]Fluciclovine PET/CT. The further analysis described a significant change in the target volume definition when the information from [¹⁸F]Fluciclovine PET/CT was included in the treatment planning. A significant change in the radiation treatment planning was reported as well by the pivotal LOCATE trial [249]. Out of 128 patients scheduled to receive radiation therapy, 65 had a major change in treatment plan involving a new treatment modality due to the results of [¹⁸F]Fluciclovine PET/CT scan.

10.4.3 Contraindications

None

10.4.4 Activities to administer

370 MBq (10 mCi). [250].

10.4.5 Dosimetry

The estimated absorbed radiation doses for adult patients following intravenous injection of[18F]Fluciclovine are shown in Table 1. Values were calculated from human biodistribution data using OLINDA/EXM (Organ Level Internal Dose Assessment/Exponential Modeling) software. The adult effective dose resulting from the administration of the recommended activity of 370 MBq of [18F]Fluciclovine is 8±1mSv. For an administered activity of 370 MBq the typical radiation doses to the critical organs, pancreas, the cardiac wall and uterine wall are 38±11mGy, 19±4mGy, and 17±16mGy, respectively [251,252].

10.4.6 Interpretation criteria and major pitfalls

In general, increased uptake in soft tissue lesions is defined as uptake visually clearly above that of the bone marrow (preferred L3 vertebrae, SUVmean) for lesions larger than 1 cm longest dimension. Soft-tissue lesions which are smaller than 1 cm longest dimension are subject to partial volume effect, but in a typical location for metastases may still be interpreted as suspicious if uptake is visually equal to or approaches marrow and significantly greater than blood pool. Note that criteria for scanners with PSF algorithms or Bayesian penalized likelihood reconstruction still need to be fully explored.

Prostatectomy bed and seminal vesicles.

Sagittal and coronal images especially useful.

• Focal uptake (SUVmax) equal to or greater than bone marrow (SUVmean) is considered most characteristic for malignancy (or likely malignant, or suspicious for malignancy).
• If uptake is between blood pool and bone marrow it does not meet criteria for malignancy but may still be reported as requiring close follow-up. MR correlation is especially helpful in this situation.
•  If there is no increased uptake, findings should be reported as likely benign.
•  In seminal vesicles, with or without a prostate, symmetric bilateral uptake similar to blood pool is likely physiologic. Asymmetric seminal vesicle uptake between blood-pool and marrow may represent malignancy and MR should be considered for further evaluation.
• Uptake on anatomical correlate <1cm significantly greater than blood pool (i.e., close to bone marrow) may also be considered suspicious for malignancy; MRI correlation is suggested.

Prostate (non-prostatectomy therapy such as radiotherapy, brachytherapy, cryotherapy, or HiFU (high intensity focused ultrasound)

• Diffuse, focal, or multi-focal uptake greater than bone marrow is considered most characteristic for malignancy (or likely malignant, or suspicious for malignancy).
• Uptake between blood pool and bone marrow does not meet criteria for malignancy but may still be reported as requiring close follow-up. MR correlation is especially helpful in this situation.
• If there is no increased focal uptake, findings should be reported as likely benign.
• If anatomical correlate for a focus of [¹⁸F]Fluciclovine  can be identified and the area of uptake is small (<1 cm) and if the uptake approaches marrow and is significantly greater than blood pool, it may also be considered suspicious for malignancy. (Due to partial volume effect, the threshold is lower.)
• If calcification is associated with uptake, inflammation may be present. MR correlation is helpful in these situations.
• Note that anecdotally, median lobe uptake (central base invaginating into the bladder) has a higher false positivity due to an increased presence of prostatic hypertrophy in this region.

Lymph nodes

• Uptake in lymph nodes equal to or greater than 1 cm longest diameter with a distribution typical for recurrent prostate cancer, equal to or greater than bone marrow, is considered most characteristic for malignancy (or likely malignant, or suspicious for malignancy).
  • ​If uptake is between blood pool and bone marrow, it does not meet criteria for malignancy but may still be reported as requiring close follow-up.
  • If uptake is less than or equal to blood pool, node should be reported as likely benign
• A small node (<1 cm longest diameter), located in a distribution typical for recurrence, and has uptake that approaches, equal to, or greater than marrow (and is significantly greater than blood pool) is considered most characteristic for malignancy (or likely malignant, or suspicious for malignancy). (Due to partial volume effect, the threshold is lower.)
  • If uptake is equal to or greater than blood pool but not approaching marrow, it may be reported as not meeting criteria for malignancy but requires close follow-up.
  • If uptake is less than the blood pool, the node should be reported as likely benign
• If uptake is seen in lymph nodes with an atypical location for recurrence (e.g., inguinal, distal external iliac, hilar, and axillary nodes) it may be considered suspicious for recurrence if seen in the context of other clearly malignant diseases. Otherwise, mild symmetric uptake in atypical lymph nodes may be considered physiologic.
  • Distal external iliac nodes may also be suspicious for malignancy in isolation if uptake is greater than bone marrow and causes of false positivity are excluded such as recent procedures and/or presence of nearby vascular grafts or orthopaedic hardware.
• A necrotic node may have false negative activity.
• Suspicious appearance on anatomic imaging such as round versus curvilinear nodes, grouped versus isolated nodes should be considered as factors in the interpretation of borderline lesions.

Bones

• Focal uptake clearly present on MIP or PET images is considered suspicious for malignancy.
• Lytic lesions tend to have greater uptake than sclerotic lesions.
• If a suspicious abnormality is seen on CT such as sclerosis without uptake, this could represent a false negative finding and further evaluation with alternative imaging modalities should be considered (MRI, NaF(¹⁸F) PET/CT, conventional bone scan SPECT/CT or PSMA if approved for use).
• Compared with FDG, of[¹⁸F]Fluciclovine has greater physiologic bone marrow heterogeneity. Careful PET windowing is helpful. Increased uptake in bone may be present after trauma (including compression fractures).
• Areas of normal bone marrow regeneration (e.g., pelvis and proximal femurs) may also show increased physiologic uptake; consider MRI if no clear CT correlate, especially if the lesion is solitary [238].

Liver

• Focal uptake in the liver greater than normal liver tissue is considered suspicious for malignancy. Focal activity less than normal liver (relatively photopenic)but higher than bone marrow may also represent malignancy and should be further evaluated with anatomical imaging [250].

Incidental Findings Normal Variants, and Important Pitfalls

In the prostate gland potential reasons for false positive uptake, include benign prostatic hyperplasia and post-radiation inflammation and fibrosis [253,254].

FP uptake in nodes may be due to acute and chronic inflammation and infection, especially if symmetric and in atypical locations for prostate cancer spread.

[¹⁸F]Fluciclovine can be taken up by other cancer cells such as breast cancer, lung cancer, colon cancer, lymphoma, hepatocellular carcinoma, multiple myeloma, squamous cell carcinoma of the scalp, and primary and metastatic tumours in the brain among others [255–262]. Uptake in renal masses should be further investigated.

Benign bone lesions such as osteoid osteoma may have moderate uptake. Mild uptake may be seen in degenerative disk and facet disease. Intense though benign activity within a joint or at a muscular insertion has occasionally been observed. Benign meningioma may have intense uptake [263]. Pituitary and adrenal adenomas can have focal uptake greater than surrounding tissue.

10.4.7 Patient preparation

Patients should not undertake any significant exercise for at least a day before the [¹⁸F]Fluciclovine PET/CT, because following strenuous exercise there is an increase in the rate of protein synthesis and degradation and of amino acid transport which may cause an increase muscle uptake of [¹⁸F]Fluciclovine .

Patients should fast for at least 4 hours prior to the scan. They may, however, drink sips of water if needed for administration of medications and to avoid dryness of the mouth. The patient should be asked not to void 30-60 minutes prior to injection unless it would prevent the patient from remaining still or completing the imaging.

The patient should be encouraged to be well-hydrated and urinate frequently during the first hours after the scan in order to reduce radiation exposure of the bladder [250].

10.4.8 Method

[¹⁸F]Fluciclovine should be administered as a bolus intravenous injection by appropriately qualified healthcare professionals. The recommended maximum volume of injection of the undiluted product is 5 mL, however, it can be diluted with sodium chloride 9 mg/ml (0.9%) solution by a factor of 8 (dilution 1+7). The injection should be followed by an intravenous flush of sterile sodium chloride 9 mg/ml (0.9%) solution to maximize the use of dispensed activity. The recommended injected activity is 370 MBq (10 mCi). No dosage adjustment based on weight is recommended because an analysis of the potential impact of variations in body mass did not demonstrate any substantial changes in the effective radiation dose. In addition, no dosage adjustment is required for the elderly population. For the current indication of prostate cancer, there is no use of [¹⁸F]Fluciclovine in children and adolescents [250].