Molecular Imaging of Prostate Cancer with PET

GLUCOSE METABOLISM

A hallmark of cancer is the Warburg effect of elevated glucose metabolism in malignant tissue relative to normal tissue. This forms the basis for increased accumulation of ¹⁸F-FDG in cancer (5). However, ¹⁸F-FDG uptake in tissue is not specific for cancer and benign conditions may also display high tracer localization. ¹⁸F-FDG PET/CT is generally limited in the detection and initial staging of primary prostate cancer because many primary tumors are small, slow-growing, well-differentiated, and multiple with low-level tumor uptake that can overlap with that of normal tissue and coexisting benign prostatic hyperplasia. Poorly differentiated tumors and prostatitis both may demonstrate high uptake.

¹⁸F-FDG PET/CT may detect occult metastatic disease in a small number of men who present with biochemical recurrence. It has restricted utility for the detection of local recurrence in the treated prostate bed because of overlap of uptake between recurrent tumor and posttherapy tissue changes. Furthermore, high urine activity in the nearby bladder can obscure local tumor uptake (6). ¹⁸F-FDG PET/CT may be most useful in the evaluation of the extent and treatment response of castrate-resistant metastatic disease (7).

LIPOGENESIS

Malignancy-induced increased cellular membrane synthesis is the basis for imaging prostate cancer with ¹¹C-acetate, ¹¹C-choline, and ¹⁸F-fluorocholine PET radiotracers (8). Acetate is transported across the cellular membrane through monocarboxylate transporter and participates in the de novo synthesis of fatty acids from acetyl-CoA and malonyl-CoA through the action of fatty acid synthase, which is upregulated in prostate cancer (9). Choline enters the cell via choline transporters and is used for biosynthesis of phosphatidylcholine in the tumor cell membrane through malignancy-induced overexpression of choline kinase (9). Similar to ¹⁸F-FDG, uptake of radiolabeled acetate and choline derivatives by the primary prostate tumor may overlap with that of benign prostatic hyperplasia and normal prostate gland tissue.

¹¹C-acetate may be useful for pelvic nodal staging and treatment planning in men with intermediate-risk (T2b–T2c or Gleason score 7 or PSA 10–20 ng/mL) to high-risk (T3a or Gleason score 8–10 or PSA > 20 ng/mL) prostate cancer (10). ¹¹C-acetate may also be useful in the localization of tumor recurrence in men with biochemical failure, with a detection rate that tends to be positively associated with increasing serum PSA level (11).

Both ¹¹C-choline and ¹⁸F-fluorocholine have received much attention over the past several years, particularly in Europe and Japan, for imaging of men with prostate cancer. Recently, ¹¹C-choline was approved by the Food and Drug Administration for production and use to detect recurrent prostate cancer at the Mayo Clinic in Rochester, Minnesota (12). ¹¹C-choline has the advantage of low excreted urine activity if scanning is performed sufficiently early after radiotracer injection, whereas ¹⁸F-fluorocholine has the advantage of longer half-life that facilitates regional tracer distribution without the need for on-site cyclotron and radiochemistry facilities.

A systematic review and metaanalysis by Umbehr et al. of ¹¹C-choline and ¹⁸F-fluorocholine PET for the initial staging of prostate cancer reported a pooled sensitivity and specificity, on a per-patient basis (10 studies, n = 637 patients), of 84% (95% confidence interval [CI], 68%–93%) and 79% (95% CI, 53%–93%), respectively (13). In restaging patients with biochemical recurrence, the metaanalysis demonstrated, on a per-patient basis (12 studies, n = 1,055 patients), a pooled sensitivity and specificity of 85% (95% CI, 79%–89%) and 88% (95% CI, 73%–95%), respectively (13).

Evangelista et al. published a systematic review and metaanalysis (19 studies, including 12 studies for all sites of disease, 3 for lymph node metastases, and 4 for local recurrence, n = 1,555 patients) of the use of choline PET and PET/CT in biochemical relapse of prostate cancer (14). This metaanalysis reported a pooled sensitivity of 85.6% (95% CI, 82.9%–88.1%) and pooled specificity of 92.6% (95% CI, 90.1%–94.6%) for all sites of disease (prostatic fossa, lymph nodes, and bone), a pooled sensitivity of 75.4% (95% CI, 66.9%–82.6%) and pooled specificity of 82% (95% CI, 68.6%–91.4%) for prostatic fossa recurrence, and a pooled sensitivity of 100% (95% CI, 90.5%–100%) and pooled specificity of 81.8% (95% CI, 48.2%–97.7%) for lymph node metastases. In the latter case, the reported perfect pooled sensitivity for detection of lymph node metastases may have been overestimated given the small number of relevant publications included in the metaanalysis.

Overall, there is limited but promising evidence for the use of choline PET/CT to stage patients with untreated, high-risk prostate cancer. Relatively robust evidence suggests that choline PET/CT can be helpful for the evaluation of locoregional and distant metastatic disease in men with biochemical relapse of prostate cancer with a detection rate that is positively associated with increasing PSA level, increasing PSA velocity, and decreasing PSA doubling time. The current recommendation is for considering choline PET/CT as the first-line diagnostic procedure in patients with biochemical relapse showing PSA levels greater than 1 ng/mL, PSA velocity higher than 1 ng/mL/y, or PSA doubling time less than 6 mo (15).

AMINO ACID TRANSPORT

Anti-1-amino-3-¹⁸F-fluorocyclobutane-1-carboxylic acid (anti-¹⁸F-FACBC) is a synthetic nonmetabolized amino acid analog that accumulates in prostate cancer via overexpression of the ASC (alanine, serine, and cysteine) transport system and other amino acid transport systems (16). The early studies of anti-¹⁸F-FACBC in prostate cancer have been encouraging and demonstrate an advantage over ¹¹¹In-capromab pendetide scintigraphy with relatively high tumor uptake and little urinary excretion of the tracer (Fig. 1) (17). A recent study suggested that anti-¹⁸F-FACBC may be advantageous over ¹¹C-choline for localization of disease in biochemical failure (18). On the basis of the early encouraging results, additional studies will be needed in a larger cohort of patients to decipher the exact role of anti-¹⁸F-FACBC in the imaging evaluation of patients with prostate cancer.

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FIGURE 1.

A 67-y-old man with biochemical recurrence of prostate cancer. Axial PET (A) and axial fused PET/CT (B) images show intense localization of anti-¹⁸F-FACBC in metastatic left external iliac nodal basin (arrow). Axial SPECT (C) and axial fused PET/CT (D) demonstrate only low-grade activity on ¹¹¹In-capromab pendetide scintigraphy. (Reprinted with permission of (26).).

ANDROGEN RECEPTOR

¹⁸F-fluoro-5α-dihydrotestosterone (¹⁸F-FDHT) is a labeled analog targeting the androgen receptor, which plays an important role in the development, growth, and maintenance of the prostate gland. Studies of comparisons to ¹⁸F-FDG have suggested that there may be diverse metabolic phenotypes of castrate-resistant cancers (androgen receptor–predominant, glycolysis-predominant, or androgen receptor/glycolysis-concordant) and that ¹⁸F-FDHT is probably suited as a pharmacodynamic response marker, rather than a treatment response marker, in the phase 1 clinical trials of new antiandrogenic drugs (19).

PSMA

PSMA is a type II cell surface transmembrane glycoprotein (also known as folate hydrolase I or glutamate carboxypeptidase II) that is upregulated in prostate cancer and provides a rational target for diagnostic imaging and directed therapy. PSMA does not have a known naturally occurring ligand, and despite what is implied from the label, it has a low degree of expression in the small intestine, proximal renal tubule, salivary glands, brain, and neovasculature of some nonprostate tumors (e.g., kidney, bladder, pancreas, lung). Investigators have developed and evaluated, in preclinical animal and pilot human studies, several radiolabeled ligands using various platforms that include antibodies or antibody fragments targeting the intracellular (binding to apoptotic or necrotic cells) or extracellular (binding to viable cells) motifs of the antigen. These PSMA-based radiotracers include ⁸⁹Zr-desferrioxamine B (DFO)-7E11; ⁶⁴Cu-labeled aptamers; and ¹¹C-, ¹⁸F-, ⁶⁸Ga-, ⁶⁴Cu-, and ⁸⁶Y-labeled low-molecular-weight inhibitors of PSMA including ¹⁸F-labeled N-[N-[(S)-1,3-dicarboxypropyl] carbamoyl]-4-[¹⁸F]fluorobenzyl-l-cysteine and ¹⁸F-labeled phosphoramidate peptidomimetic with some formulations that can also be labeled with radionuclides such as ¹⁷⁷Lu or ⁹⁰Y for targeted radioimmunotherapy (Fig. 2) (20).

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FIGURE 2.

Anterior PET maximum-intensity-projection image obtained at 2 h after intravenous injection of ¹⁸F-DCFBC (N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-¹⁸F-fluorobenzyl-l-cysteine)demonstrate normal biodistribution of this low-molecular-weight, urea-based inhibitor of PSMA and high focal accumulation (arrows) in bone (A) or nodal metastases (B) from prostate cancer. (Reprinted with permission of (27).).

BONE MATRIX

The bone uptake of ¹⁸F-NaF is related to chemisorption with exchange of ¹⁸F⁻ ion for OH⁻ ion on the surface of the hydroxyapatite matrix of bone to form fluoroapatite and migration of ¹⁸F⁻ ion into the crystalline matrix of bone. ¹⁸F-NaF PET/CT has been shown to provide higher sensitivity and specificity than ^99mTc-based planar and single-photon CT bone scintigraphy for detection of osseous metastases in men with prostate cancer (21). The clinical use of ¹⁸F-NaF PET/CT is projected to grow on the basis of increasing availability of PET/CT scanners, commercial regional distribution of ¹⁸F-labeled radiotracers, lingering uncertainty on the supply of ^99mTc-labeled compounds, and the recent decision by the Center for Medicare and Medicaid Services for scan reimbursement through participation in the National Oncologic PET Registry.

OTHER PROMISING BIOMARKERS

Several other approaches are also in the preclinical stages of development and testing for molecular imaging of prostate cancer with PET. For example, ⁶⁸Ga-DOTA-CHCO-Gly-4-aminobenzyl-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH is a radiolabeled ligand based on bombesin, which is an amino acid analog of the human gastrin-releasing peptide that binds to the GRPR. GRPR is overexpressed in prostate cancer.

Researchers have also developed radiolabeled ligands targeting free PSA (e.g., ⁸⁹Zr-5A10 monoclonal antibody), prostate stem cell antigen (PSCA) (e.g., ¹²⁴I-anti-PSCA antibody fragments), and thymidine kinase for assessing cellular proliferation and cellular stress (e.g., 1-(2′-deoxy-2′-fluoro-b-d-arabinofuranosyl)thymidine). There have also been reporter gene–reporter probe approaches for direct visualization and characterization of sentinel lymph nodes in prostate cancer using the reporter gene herpes simplex virus type 1 TK and reporter probe 9-(4-¹⁸F-fluoro-3-[hydroxymethyl]butyl)guanine (22).

POTENTIAL OPPORTUNITIES WITH PET/MR IMAGING

PET/MR imaging provides combined structural, metabolic, and functional imaging information that can potentially affect patient management and outcome. It may also enhance patient convenience by providing a 1-stop diagnostic imaging work-up, reducing patient anxiety, total scan time, and recalls for repeated scanning (23). Simultaneous acquisition of multiparametric MR and PET images with an appropriate radiotracer may be particularly valuable for identifying high-yield candidate biopsy sites that could reduce false-negative initial and repeated biopsies. Moreover, combined PET/MR imaging could facilitate the use of targeted focal therapy and the determination of its efficacy (Fig. 3) (24). Another interesting prospect is the potential utility of dual-modality imaging agents in this clinical setting (25).

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FIGURE 3.

Fused multiparametric MR imaging and PET with ¹¹C-choline in patient with true-positive high-grade (Gleason 4 + 3) left lobe (red arrows) and false-negative low-volume intermediate-grade (Gleason 3 + 3) right lobe (blue arrows) prostate cancer. (A) T2-weighted MR image. (B) Fused ¹¹C-choline PET and T2-weighed MR image. (C) Apparent diffusion coefficient map obtained from diffusion-weighted image coregistered over T2-weighted MR image. (D) Hematoxylin and eosin histology slice. (E) Histology slice coregistered over T2-weighted MR image. (F) Parametric fusion PET/MR image using P_CHOL/ADC ratio defined as quotient of standardized uptake value over apparent diffusion coefficient values. ADC = apparent diffusion coefficient; CHOL = choline; HE = hematoxylin and eosin. (Reprinted with permission of (28).).