Download New Agents and Techniques for Imaging Prostate Cancer

F O C U S O N MO L E C U L A R I M A G I N G
New Agents and Techniques for Imaging Prostate
Cancer
The successful management of prostate cancer requires
early detection, appropriate risk assessment and optimum
treatment. Imaging of prostate cancer has become increasingly important to predict which cancers are indolent and
which will become aggressive as the treatment may be different for different grades of the disease. Different modalities have been tested to diagnose prostate cancer accurately,
stage it and to predict its behavior before and after treatment.
This review briefly describes the key clinical issues in prostate cancer diagnosis and therapy and summarizes the various
new imaging modalities and agents in use and on the horizon.
Prostate cancer (PCa) is the most common malignancy
among men in the United States, with mortality only superseded by lung cancer, accounting for 10% of all cancer related deaths in 2008 (1). PCa is currently characterized by
its TNM stage, Gleason score, and prostate-specific antigen
(PSA) serum level. PSA testing is the mainstay of PCa detection and has resulted in down-staging of the disease at diagnosis. However, there remains growing concern regarding the
potential risk of overdiagnosis and, consequently, overtreatment of potentially indolent disease (2). PSA also lacks the
ability to differentiate low-grade from high-grade cancers. To
complicate matters, PCa is not rare among men with PSA levels that are generally thought to be in the normal range (3).
Conventional imaging such as computed tomography (CT),
magnetic resonance imaging (MRI), ultrasound (US) and bone
scan with [99mTc]MDP have been widely used in different PCa
disease states. However, those modalities do not adequately
address the overarching problem of distinguishing lethal from
non-lethal disease, a prediction of disease prognosis or that of
treatment response. A multidisciplinary approach is required to
manage PCa. At a recent workshop the National Cancer Institute proposed intervention at four different levels (4). The role
of imaging in (i) initial diagnosis, (ii) staging, (iii) disease recurrence after treatment and (iv) assessment of response to therapy
was discussed. Also discussed were the multiple new molecular
agents that are being tested and can be incorporated into the
current paradigm of diagnosis, treatment and a prompt diagnosis of recurrent disease. We will address new approaches to
imaging PCa in the context of those four levels of intervention.
Pre-diagnosis.
The current standard for diagnosing PCa is transrectal ultrasound (TRUS) guided sextant biopsy with or without addiReceived Nov. 8, 2007; revision accepted Jan. 17, 2007.
For correspondence or reprints contact: Joshua Wachtel; David Geffen
School of Medicine at UCLA, Dept. of Molecular & Medical Pharmacology, B2058L CHS: Box 956948
Tel: (310) 825.8246,
E-mail: [email protected]
COPYRIGHT ª 2008 by the Society of Nuclear Medicine, Inc.
DOI: 00.0000/jnumed.000.000000
tional biopsies. PCa is the only malignancy where the diagnosis is made from tissue obtained on a blind biopsy. Also,
the histological grade is underestimated on such biopsies. The
heterogeneous nature and multifocality of the tumor renders a
blind biopsy inadequate in assessing the grade of the disease.
Furthermore, multiple cores only sample a small percentage of
the prostate. More comprehensive data are thus required prior
to tissue sampling for a more targeted approach. MRI provides
higher spatial and contrast resolution than TRUS and CT but
lacks specificity. Magnetic resonance spectroscopy (MRS)
provides a non-invasive method of detecting molecular biomarkers of low molecular weight within the cytosol and extracellular spaces of the prostate. MRS relies upon the loss of
a normal citrate peak from the peripheral zone and an increase
in the choline peak, an indirect marker of cell death. The ratio
of (choline + creatine)/citrate (CC/C) in PCa exceeds the mean
ratio found in healthy prostate tissue. Pulsed field gradients are
generally used for localization using volumes of interest and
include point resolved spectroscopy (PRESS) and stimulated
echo acquisition mode (STEAM), well summarized in an excellent review by Mueller-Lisse et al (5). MRI combined with
MRS are superior to sextant punch biopsy with a sensitivity and
specificity of 56% and 82%, respectively, with improved diagnosis in the apex, the most difficult area to reach by punch biopsy (6). Additionally, MRS imaging measurement of prostate
tumor CC/C and tumor volume correlate with Gleason score.
A promising new indication of this method is detection and localization of PCa in previously negative TRUS-guided biopsy.
Additionally, MRS at 7T minimizes the chemical shift artifact
between citrate and choline to 5% and can be used to include the
detection of spermine next to citrate, creatine, and choline (7).
Despite the limited ability of US to delineate cancer, it has the
advantage of low cost, availability and speed over MRI-guided interventions. A recent study demonstrated the feasibility
of TRUS-MRI fusion-guided prostate biopsy, with the entire
procedure, including fusion, requiring approximately 10 min
(8). Furthermore, with the use of an ultrasound 3-D navigation
system, such as that developed by Bax et al. (9), needle guidance can be improved for sampling small lesions. Tests of the
accuracy of biopsy needle guidance in agar prostate phantoms
showed that the mean error was 2.1 mm and the 3D location
of the biopsy core was recorded with a mean error of 1.8 mm,
with less than 5% error in volume estimation. Addition of MRS
data to that multimodality approach can improve detection of
PCa by a method that can be used by urologists in their office.
Albers et al. (10) recently demonstrated very promising results by quantifying differences in hyperpolarized 13C-labeled
pyruvate and its metabolites (lactate and alanine) between the
various histological grades of PCa using the transgenic adenocarcinoma of mouse prostate (TRAMP) model (see below). It
was previously difficult to observe lactate and alanine with in
GENERIC RUNNING TITLE • Wachtel et al.
1
Figure 1. T2-weighted 1H MR image depicting low-grade primary
tumor in a TRAMP mouse (A), overlay of an interpolated hyperpolarized
13C-lactate image (B), and the spectral grid (C) and (D). The spectrum
shows prominent signals from lactate and pyruvate and smaller signals
from alanine and pyruvate hydrate. [Adapted with permission from (10)]
vivo MRS studies, as the lipids resonate near the frequencies
of these metabolites. However, 13C-labeled substrates have
recently been polarized using dynamic nuclear polarization
(DNP) to obtain tens of thousands fold enhancement of the
13C-NMR signals for the substrate and its metabolites. This
method allows three dimensional visualization of the distribution of lactate, pyruvate and alanine throughout the prostate
and surrounding anatomy, providing a non-invasive method
not only to detect tumors and regional lymph node metastasis but also to demonstrate a strong correlation between metabolite levels and the grade of the tumor (Figures 1 and 2).
This technique, if successful in humans, has the potential to
predict which tumors will be indolent and which will progress
to invasive, metastatic disease. A phase 1 clinical trial will be
under way in PCa patients in the spring of 2009. A commercial DNP polarizer for human studies will be available in 2010.
Methylcholine labeled with carbon-11 ([11C]choline) has
been tested as a new PET radiopharmaceutical (11). The radiotracer is integrated into phospholipids in the cell membrane
of tumor cells and its uptake in tumors represents the rate of
tumor cell replication. Testa et al. showed that for detection
and localization of primary prostate cancer, [11C]choline PET/
CT was found to have lower sensitivity compared to 3D MRS
alone or in conjunction with MRI imaging (3D MRS 81%, 3D
MRS and MRI 88%) (12). The specificity for detection and
localization were, however, comparable with the three modalities. A high uptake of [11C]choline characterizes not only
carcinomatous but also hyperplastic prostate tissue (11). In a
recent study no significant correlation was detected between
[11C]choline standardized uptake value (SUVmax) and PSA
levels, Gleason score or pathological stage (13). The short
physical half-life of carbon-11 has led to the development of an
18F-labeled analog of choline. Kwee et al. showed that [18F]
fluorocholine can localize dominant areas of malignancy, but
may miss smaller tumor foci, demonstrating SUVmax ¡Ý 5.6
(sensitivity 64%, specificity 90%, accuracy 72%) (14). However, Igerc et al. showed only a 25% detection rate of focal [18F]
fluorocholine guided biopsy resulting in detection of PCa (15).
They also showed that delayed imaging with [18F]fluorocholine did not result in the ability to differentiate malignancy from
normal tissue or benign processes. The evaluation of [11C]acetate PET for primary PCa localization has not been reported.
Initial experience with the positron emission tomography (PET) agent, anti-1-amino-3-18F-fluorocyclobutane-1carboxylic acid (anti-[18F]FACBC), a synthetic L-leucine
analog, in 15 patients with either newly diagnosed or suspected recurrent PCa, has been encouraging (16). In newly
diagnosed patients, anti-[18F]FACBC correctly identified tumor in 40 of 48 prostate region sextants, with seven out of
nine patients demonstrating pelvic nodal uptake concordant
with the clinical follow-up. Anti-[18F]FACBC was positive
in all four patients with proved recurrence (negative ProstaScint. scans in three of these patients) and was instrumental in directing biopsy to prove neoplastic recurrence in one
patient in whom lymph nodes were not obviously enlarged.
Initial staging.
The TNM system describes the extent of the primary tumor
within the gland as well as within extraglandular tissue, spread
to lymph nodes and the presence of more distant metastases. Patients with organ-confined disease tend to do better than those
with extraglandular disease. The approach of combining dynamic contrast-enhanced MRI with T2-weighted MRI at 1.5T
and high-spatial-resolution has a specificity of 95% for the detection of extracapsular disease with a sensitivity of 86% (17).
The presence of pelvic lymph node metastases is considered the strongest predictor of disease recurrence and progression, and the presence of metastases often means the difference between local and systemic therapy. The conventional
criteria based on size and shape of the nodes cannot determine
the presence of micrometastases within the lymph nodes. The
use of lymphotropic ultrasmall superparamagnetic particles of
iron oxide (USPIO) as a contrast agent for MRI enables reliable detection of metastases in normal-sized pelvic lymph
nodes of patients with PCa. USPIO particles are consumed by
macrophages in normal lymph nodes resulting in a signal decrease on T2/T2*-weighted MRI sequences and demonstrate
extremely high sensitivity (100%) and specificity (96%) for
lymph nodes measuring between 5 mm and 1 cm in diameter,
dropping to 41% for nodes less than 5 mm (18) in diameter.
However, the interpretation of this technique is time consuming, since a node-by-node comparison must be made between
the native MRI and a second MRI after USPIO administration.
Diffusion-weighted imaging (DWI) is an MRI technique
based on the detection of random movement of water molecules that is theoretically lower in cancers showing high cellular density, higher Gleason score (19) or tissue heterogeneity.
An apparent diffusion coefficient (ADC) is calculated on the
basis of the combination of this measurement, which is lower
in PCa compared to the normal tissue. In patients with lowrisk, localized disease, tumor ADC may be a useful marker of
PCa progression and may help to identify patients who stand
to benefit from radical treatment. There is a recent trend toward the use of two or more functional imaging sequences,
especially since the advent of DWI, which is fast and does not
require exogenous contrast. Studies that combine DWI with
2 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 99 No. 1 • June 3001
T2-weighted, postcontrast and MRS techniques show promising results (20). Diffusion-weighted sequences are typically T2/T2*-sensitive and potentially allow combination of
cellular information with USPIO uptake in the same examination. The combination of reduced diffusion together with
relatively unchanged T2/T2* after USPIO administration in
malignant lymph nodes leads to hyperintense signal suggesting
that USPIO-enhanced MRI in combination with DW-MRI is
an accurate method for detecting pelvic lymph node metastases. Xu et al. (21) recently obtained diffusion tensor imaging
measurements of PCa performed in vivo in patients undergoing radical prostatectomy, and later, ex vivo, in the same patients’ prostatectomy specimens. The results showed that the
ADC contrast parallels the T2W contrast with ADC being
more specific than T2W contrast for peripheral zone PCa. Diffusion anisotropy provides a unique contrast that differentiates
stromal benign prostatic hypertrophy from PCa in the central
gland, while its utility for PCa in the peripheral zone is limited.
Disease recurrence after therapy.
Biochemical recurrence occurs in 20-40% of patients within
10 years of ¡°definitive¡± PCa therapy, often preceding clinically detectable disease (22). Accurate delineation of local
versus distant metastatic disease is imperative to determine
appropriate therapy. PCa grows slowly and is rarely avid for
[18F]fluorodeoxyglucose (FDG). Also, the bladder produces a
very strong FDG signal near the prostate. The role of [11C]
choline, as previously described, is limited in detecting early recurrence due to its inability to detect microscopic foci
of metastatic PCa (23). Although higher urinary excretion
by the fluorinated analogs represents a disadvantage in imaging PCa, [18F]fluorocholine PET-CT has demonstrated a
sensitivity of 71% in localizing recurrent disease (24). [11C]
Acetate has also been evaluated for detection of tumor recurrence and overall has demonstrated results comparable
to those of [11C]choline, as reviewed by Morris et al. (25).
The prostate-specific membrane antigen (PSMA) is upregulated in PCa, particularly in advanced, hormone-independent
and metastatic disease. PSMA is an integral membrane protein with an enzymatic active site in an extracellular domain,
which makes this an excellent target for imaging and therapy.
ProstaScintTM, a monoclonal antibody-based PSMA imaging agent, was previously developed but has demonstrated
limited clinical utility (26). Other PSMA-binding antibodies
are under development for imaging, and may prove superior
to ProstaScintTM (27). Urea-based low molecular weight
agents of high affinity and in vivo selectivity for PSMA
have been synthesized using a variety of radionuclides for
positron emission tomography (PET) and single photon computed tomography (SPECT) (28), (29). Compounds of this
class demonstrate very high target to non-target ratios and
rapid washout kinetics in both preclinical models (Figure 3)
and in a phase I study (30). Initial indications for the use of
these agents would be for staging and in patients who have
undergone prostatectomy who later present with a rising PSA.
Therapeutic monitoring.
1-(2¡¯-Deoxy-2¡¯-fluoro-¦Â-D-arabinofuranosyl)thymidine
(FMAU) is a thymidine analog that can be phosphorylated by thymidine kinase and incorporated into DNA. This agent has been
evaluated for imaging PCa in three patients. FMAU demonstrated low uptake in a previously radiated prostate bed. Standardized
uptake values ranging from 2.89 to 4.49 were seen in the tumor.
Bone metastasis also showed high radiotracer uptake. Low urinary bladder radioactivity was seen despite renal excretion (31).
16¦Â-[18F]Fluoro-5¦Á-dihydrotestosterone (FDHT), an analog of 5¦Á-dihydrotestosterone, has been evaluated to study
the binding selectivity of FDHT in patients with PCa (32).
Patients with a positive study underwent a repeat examination after the administration of flutamide, an antiandrogen, and
demonstrated interval decrease in tumor uptake, suggesting
FDHT to be potentially useful for evaluating the availability
and functional status of tumor androgen receptors to monitor
therapeutics that target them. Future studies are needed to investigate whether androgen receptor availability as assessed
by FDHT-PET is predictive of response to hormonal therapy.
There has been a renewed interest in the use of [18F]NaF PET
imaging for early detection of metastases. A recent study has
shown this agent to be superior to [99mTc]MDP planar bone
scan, with or without SPECT, in detecting metastatic disease (33).
Molecular genetic imaging provides a way to monitor gene
therapy, especially to determine the level and volume of
therapeutic gene expression that can be correlated with clinical outcome. Barton et al. (34) recently conducted a phase 1
study demonstrating the feasibility of adenovirus-mediated
gene therapy for PCa. They developed a methodology based
on the sodium iodide symporter (NIS). Patients with clinically localized PCa were administered a replication-competent
adenovirus, Ad5-yCD/utTKSR39rep-hNIS, armed with two
suicide genes and the NIS gene via an intraprostatic injection.
NIS gene expression was imaged noninvasively by uptake of
[99mTc]NaTcO4 in infected cells using SPECT, which showed
a peak gene expression volume at one to two days after the
adenovirus injection and was detectable in the prostate for
Figure 2. Dual pinhole SPECT-CT
of PC-3 PIP (PSMA+) and PC-3 flu
(PSMA-) tumor bearing mouse with
[99mTc]L1. Note lack of radiopharmaceutical outside of tumor. [Adapted
with permission from (29)]
GENERIC RUNNING TITLE • Wachtel et al.
3
up to seven days. Whole-body imaging showed intraprostate
gene expression, without evidence of extraprostate dissemination of the adenovirus by SPECT imaging, demonstrating the feasibility of this technology in humans (Figure 4).
Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide receptor VPAC1 are overexpressed in 100% of human PCa (35). [64Cu]TP3939, a VIP
analog labeled with the positron-emitting radionuclide 64Cu,
specifically targets VPAC1 receptors for PET visualization
of PCa. Copper-64, with a physical half-life of 12.7 h (¦Â+ =
655 keV [17. 4%]; ¦Â¨C = 573 keV [30%]), is commercially
available, has well known chemistry, provides quantitative
yields, and permits the use of radiolabeled compounds without further purification (35). [64Cu]TP3939 was tested in
PCa xenografts in athymic nude mice and spontaneous PCa
in TRAMP mice (see below). The compound demonstrated
a high target to background ratio at 24 hours after injection
and is a promising agent not only for imaging PCa but also
for detecting its recurrence, detecting metastatic lesions, and
determining the effectiveness of therapeutic intervention.
Although we have focused on new agents and technique for
clinical use in PCa, preclinical models, which are continually
increasing in relevance to human disease, have proved critical in the development of new molecular imaging agents for
PCa. The current state of relevant preclinical models to study
tumorogenesis and to develop effective prevention strategies and therapeutic interventions has been described by Pienta et al. (36). That description includes the TRAMP model,
which shows a histopathologic disease progression and associated metabolic changes that mimic the human disease.
Additionally, researchers have applied tools used to study
tumor biology, including the insertion of the VEGF-C gene
into well known cell lines, which promotes lymphangiogenesis causing the cells to metastasize (37). Those highly
Atif Zaheer, Steven Y. Cho, Martin G. Pomper
Johns Hopkins Medical Institutions, Baltimore, MD
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relevant preclinical models have and will continue to hasten the development of molecular imaging agents for PCa.
Perspective.
Anatomic localization and assessment of disease aggressiveness play key roles in determining prognosis and in
guiding the therapy of PCa. Multiple, new promising noninvasive diagnostic tools have the ability to provide that information, and are continually emerging. As new, selective
biomarkers, such as the recently described stage-dependent
urinary marker sarcosine (38), are discovered, coupling
them with molecular imaging tools will avert unnecessary
surgeries and prolong survival. In the future, disease assessment will depend on a multimodality imaging approach
tailored to each patient for maximum therapeutic benefit.