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.
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.
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. Currently, the prostate is imaged using an endorectal coil combined with four external coils. 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. 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. 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. 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.
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.