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Spectroscopy in Prostate Cancer: Hope or Hype?

Spectroscopy in Prostate Cancer: Hope or Hype?

ABSTRACT: Clinical applications of image-based radiation therapy for the study of prostate cancer have expanded significantly over the past years. The results of recent studies of magnetic resonance imaging (MRI) combined with magnetic resonance spectroscopic imaging (MRSI) demonstrate that the MRI/MRSI exam is a unique method by which to noninvasively study the cellular metabolism and anatomy of the prostate. This technology has the potential to define the tumor volume through functional or metabolic imaging. The results of current MRI/MRSI studies also provide evidence that the magnitude of metabolic changes in regions of cancer before therapy, as well as the extent of the time course of metabolic changes after therapy, may improve our understanding of cancer aggressiveness. Assessment of cancer spread outside the prostate can be significantly improved by combining MRI findings with estimates of metabolic abnormalities provided by MRSI. Clinically, combined MRI/MRSI has already demonstrated a potential for improved diagnosis, staging, and treatment planning for patients with prostate cancer. Additional studies will reveal both the positive aspects and clinical challenges of MRI/MRSI as an emerging technique with great potential for clinically meaningful outcomes in the future. [ONCOLOGY 15:1399-1418, 2001]

Image-based therapy is not only a buzzword for
researchers but a major key to the future of cancer staging and therapy. Knowing
the precise distribution of a patient’s cancer enables clinicians to determine
whether a cure is possible with local therapy alone. A true stage T1 lesion
could be excised without the necessity of adjuvant therapy. Radiation fields and
surgical approaches could be designed to minimize complications. A more accurate
estimate of prognosis could facilitate the design of prospective clinical
trials. With better modeling, trials could be completed more quickly with fewer
patients, thus reducing cost and follow-up time.

Advances are being pioneered in just about every area of imaging. Despite
these advances, imaging is still hampered by the poor spatial resolution of
modalities that are based on measurements of differences in density or structure
that originate from the atomic number, the hydrogen concentration, or the
concentration of an antigen or metabolic by-product.

Magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging
(MRSI), collectively called MRI/MRSI, represent one of the most exciting avenues
currently being pursued at numerous institutions throughout the country. This
strategy takes advantage of the two different approaches: MRI provides excellent
spatial resolution and MRSI delineates the metabolic activity of differentiated
soft tissue. This article summarizes the current state of this technology as it
applies to the management of prostate cancer. It is our view that this approach
offers more hope than hype.

Understanding the MRI/MRSI Exam

More than 2,500 prostate cancer patients have been imaged at the University
of California, San Francisco (UCSF) since development of the combined MRI/MRSI
exam for staging. The exam is performed using a standard clinical 1.5-T magnetic
resonance scanner applied through commercially available coils. A commercial
package is being developed that allows the MRI/MRSI exam to be performed in
routine clinical practice.

A multi-institutional clinical trial to test the robustness and clinical
significance of combining metabolic and anatomic information for localizing and
staging prostate cancer is now being planned. Therefore, it is timely to present
what is already known about combined MRI/MRSI, how this technology is currently
being used in the clinic, and how it might be used in the future.

Basic Principles

Magnetic resonance imaging is a noninvasive technique that uses strong
magnetic fields and radiofrequency waves to obtain morphologic images based on
physical properties (ie, T1 and T2 relaxation times) of water contained in body
tissues. Magnetic resolution images, especially high spatial resolution
endorectal coil T2-weighted images, provide an excellent depiction of prostatic
zonal anatomy, the urethra, neurovascular bundles, surrounding soft tissues, and
prostate cancer.[1] Currently, the prostate is imaged using an endorectal coil
combined with four external coils.[2] The endorectal coil provides the
sensitivity necessary for acquiring prostate imaging and MRSI data, while the
pelvic-phased array of four external coils allows a field of view large enough
to assess pelvic lymph nodes and bones for metastatic disease.

On T2-weighted images, regions of cancer within the prostate demonstrate
lower signal intensity relative to healthy peripheral zone tissue owing to loss
of normal ductal morphology and associated long-T2 water (Figure
1
). The
anatomic information provided by MRI has demonstrated utility as a staging
modality for the differentiation between organ-confined cancers and those with
extracapsular extension.[1,3-5] The use of fast spin echo imaging and a pelvic
phased-array incorporating an endorectal coil can markedly improve the
evaluation of extracapsular extension (accuracy: 81%; sensitivity for
extracapsular extension: 91%) and seminal vesicle invasion, thereby improving
the staging of prostatic cancer.[1] The use of fast spin echo imaging has also
reduced the MRI exam time from over 60 minutes to less than 30 minutes, thereby
allowing the addition of MRSI to clinical MRI exams.

With the emergence of disease-targeted therapies such as interstitial
brachytherapy and intensity-modulated radiotherapy (IMRT), the assessment of
prostate cancer location and extent has become an important consideration in
treatment selection and planning. Studies evaluating clinical data (eg, digital
rectal examination, prostate-specific antigen [PSA], and PSA density),
systematic biopsy, transrectal ultrasound, and MRI have so far shown
disappointing results for tumor localization within the prostate.[6-9]
High-resolution endorectal-pelvic-phased array MRI has demonstrated good
sensitivity (78%) but low specificity (55%) in identifying tumor location
because of a large number of false-positives.[1] These false-positives can be
attributed to factors other than cancer, including postbiopsy hemorrhage,
prostatitis, and therapeutic effects that can cause imaging appearances similar
to prostate cancer.[9,10] An accurate assessment of the presence and extent of
cancer requires additional methods such as functional or metabolic imaging of
the prostate.

Addition of MRSI

The recent development of MRSI expands the diagnostic assessment of prostate
cancer beyond the morphologic information provided by MRI.[11-13] As with MRI,
MRSI uses a strong magnetic field and radio waves to noninvasively obtain
metabolic spectra based on the relative concentrations of cellular chemicals.
With MRSI, specific resonances (peaks) for the metabolites citrate, choline,
creatine, and various polyamines from contiguous small volumes throughout the
gland are observed (Figure 2).

The peaks for these different chemicals occur at distinct frequencies or
positions in the MRSI spectrum. The areas under these peaks are related to the
concentration of the respective metabolites, and changes in these concentrations
can be used to identify cancer with reasonably high specificity.[13] As seen in
Figure 2
, prostate cancer (right side of image) can be metabolically
discriminated from the healthy peripheral zone (left side of image) based on
significant decreases in citrate and polyamines and an increase in choline.

Biochemical Mechanisms

Many of the biochemical mechanisms that result in these metabolic changes are
known. The decrease in citrate with prostate cancer is due to both changes in
cellular function[14,15] and changes in the organization of the tissue, which
loses its characteristic ductal morphology. [16,17] The elevation of the choline
peak in prostate cancer is associated with changes in cell membrane synthesis
and degradation that occur with the evolution of human cancers.[18,19] The
polyamines spermine, spermidine, and putrescine also are abundant in healthy
prostatic tissues and reduced in cancer. Polyamines have been associated with
cellular differentiation and proliferation.[20,21]

The high specificity of spectroscopy arises from the observation of multiple
metabolic changes within the same spectrum. To enhance the display of the
metabolic data and to correlate it with the prostatic anatomy and pathology,
spectral arrays with metabolite peak areas and ratios can be displayed
simultaneously with the corresponding magnetic resonance image (Figure
3
). Thus,
maps of metabolite concentrations can be overlaid on the corresponding anatomic
images (Figure 4). Because the same gradients are used for imaging and
spectroscopy acquisitions, the data sets are already in alignment and can be
directly overlaid. In this manner, areas of anatomic abnormality (decreased
signal intensity on T2-weighted images) can be correlated with the corresponding
area of metabolic abnormality (increased choline and decreased citrate).

Additionally, since volume MRI and MRSI data are collected, spectral voxels
can be moved to optimally encompass the abnormality on MRI after the data are
acquired (Figure 4). This kind of interactive analysis will be the way MRI/MRSI
data are interpreted in the future and should reduce interpretive errors
associated with overlapping regions of normal and cancerous tissue.

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