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
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
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
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.
1. Hricak H, White S, Vigneron D, et al: Carcinoma of the prostate gland: MR
imaging with pelvic phased-array coils versus integrated endorectal-pelvic
phased-array coils. Radiology 193:703-709, 1994.
2. Hricak H, Dooms GC, Jeffrey RB, et al: Prostatic carcinoma: Staging by
clinical assessment, CT, and MR imaging. Radiology 162:331-336, 1987.
3. Bartolozzi C, Menchi I, Lencioni R, et al: Local staging of prostate
carcinoma with endorectal coil MRI: Correlation with whole-mount radical
prostatectomy specimens. Eur Radiol 6:339-345, 1996.
4. Chelsky MJ, Schnall MD, Seidmon EJ, et al: Use of endorectal surface coil
magnetic resonance imaging for local staging of prostate cancer. J Urol 150(2 Pt
5. Castagnola C, Marechal JM, Bouvier R, et al: Does magnetic resonance
imaging allow the assessment of the loco-regional extension of cancer of the
prostate? Report of 27 anatomoradiologic comparisons. Prog Urol 2:409-419,
6. Presti JC Jr, Hovey R, Carroll PR, et al: Prospective evaluation of
prostate specific antigen and prostate specific antigen density in the detection
of nonpalpable and stage T1C carcinoma of the prostate. J Urol 156:1685-1690,
7. Presti JJ, Hovey R, Bhargava V, et al: Prospective evaluation of prostate
specific antigen and prostate specific antigen density in the detection of
carcinoma of the prostate: Ethnic variations. J Urol 157:907-911, 1997 (see
comment in J Urol 157:907-911 [incl discussion], 1997.)
8. Sommer FG, Nghiem HV, Herfkens R, et al: Determining the volume of
prostate carcinoma: Value of MR imaging with an external-array coil. Am J
Roentgenol 161:81-86, 1993.
9. White S, Hricak H, Forstner R, et al: Prostate cancer: Effect of
postbiopsy hemorrhage on interpretation of MR images. Radiology 195:385-390,
10. Hricak H, Carrington BM: MRI of the Pelvis, pp 249-311. London, Dunitz,
11. Kurhanewicz J, Vigneron DB, Nelson SJ: Three-dimensional magnetic
resonance spectroscopic imaging of brain and prostate cancer. Neoplasia
12. Kurhanewicz J, Vigneron DB, Males RG, et al: The prostate: MR imaging and
spectroscopy. Present and future. Radiol Clin North Am 38:115-138, 2000.
13. Kurhanewicz J, Vigneron DB, Hricak H, et al: Three-dimensional H-1 MR
spectroscopic imaging of the in situ human prostate with high (0.24-0.7-cm³)
spatial resolution. Radiology 198:795-805, 1996.
14. Costello LC, Franklin RB: Concepts of citrate production and secretion by
prostate. 1. Metabolic relationships. Prostate 18:25-46, 1991.
15. Costello LC, Franklin RB: Concepts of citrate production and secretion by
prostate. 2. Hormonal relationships in normal and neoplastic prostate. Prostate
16. Kahn T, Beurrig K, Schmitz-Dreager B, et al: Prostatic carcinoma and
benign prostatic hyperplasia: MR imaging with histopathologic correlation.
Radiology 173:847-851, 1989.
17. Schiebler ML, Tomaszewski JE, Bezzi M, et al: Prostatic carcinoma and
benign prostatic hyperplasia: Correlation of high-resolution MR and
histopathologic findings. Radiology 172:131-137, 1989.
18. Aboagye EO, Bhujwalla ZM: Malignant transformation alters membrane
choline phospholipid metabolism of human mammary epithelial cells. Cancer Res
19. Daly PF, Lyon RC, Faustino PJ, et al: Phospholipid metabolism in cancer
cells monitored by 31P NMR spectroscopy. J Biol Chem 262:14875-14878, 1987.
20. Heby O: Role of polyamines in the control of cell proliferation and
differentiation. Differentiation 19:1-20, 1981.
21. Heston WD: Prostatic polyamines and polyamine targeting as a new approach
to therapy of prostatic cancer. Cancer Surv 11:217-238, 1991.
22. Yu KK, Scheidler J, Hricak H, et al: Prostate cancer: Prediction of
extracapsular extension with endorectal MR imaging and three-dimensional proton
MR spectroscopic imaging. Radiology 213:481-488, 1999.
23. Scheidler J, Hricak H, Vigneron DB, et al: Prostate cancer: Localization with three-dimensional proton MR
spectroscopic imaging-clinicopathologic study. Radiology 213:473-480, 1999.
24. Wefer AE, Hricak H, Vigneron DB, et al: Sextant localization of prostate
cancer: Comparison of sextant biopsy, magnetic resonance imaging and magnetic
resonance spectroscopic imaging with step-section histolog. J Urol 164:400-404,
2000 (see comment in J Urol 164:400-404, 2000).
25. Kaji Y, Kurhanewicz J, Hricak H, et al: Localizing prostate cancer in the
presence of postbiopsy changes on MR images: Role of proton MR spectroscopic
imaging. Radiology 206:785-790, 1998.
26. D’Amico AV, Schnall M, Whittington R, et al: Endorectal coil magnetic
resonance imaging identifies locally advanced prostate cancer in select patients
with clinically localized disease. Urology 51:449-454, 1998.
27. Bates TS, Gillatt DA, Cavanagh PM, et al: A comparison of endorectal
magnetic resonance imaging and transrectal ultrasonography in the local staging
of prostate cancer with histopathological correlation. Br J Urol 79:927-932,
28. Presti JC, Hricak H, Narayan PA, et al: Local staging of prostatic
carcinoma: Comparison of transrectal sonography and endorectal MR imaging. AJR
Am J Roentgenol 166:103-108, 1996
29. Rorvik J, Halvorsen OJ, Albreksten G, et al: MRI with an endorectal coil
for staging of clinically localized prostate cancer prior to radical
prostatectomy. Eur Radiol 9:29-34, 1999.
30. Ikonen S, Karkkainen P, Kivisaari L, et al: Magnetic resonance imaging of
clinically localized prostate cancer. J Urol 159:915-919, 1998.
31. Bates TS, Cavanagh PM, Speakman M, et al: Endorectal MRI using a 0.5
T midfield system in the staging of localized prostate cancer. Clin Radiol
32. Perrotti M, Kaufmann RP Jr, Jennings TA, et al: Endorectal coil magnetic
resonance imaging in clinically localized prostate cancer: Is it accurate? J
Urol 156:106-109, 1996.
33. Sheu MH, Wang JH, Chen KK, et al: Prostate cancer: Local staging with
endorectal magnetic resonance imaging. Zhonghua Yi Xue Za Zhi (Taipei)
34. McNeal JE, Alrot J, Villers A, et al: Mucinous differentiation in
prostatic adenocarcinoma. Hum Pathol 22:979-988, 1991.
35. Roach M, Walner K: Prostate cancer, in Leibel S, Phillips TL (eds):
Textbook of Radiation Oncology, 1st ed, pp 744. Philadelphia, WB Saunders Co,
36. Roach M III, Faillace-Akazawa P, Malfatti C, et al: Prostate volumes
defined by magnetic resonance imaging and computerized tomographic scans for 3-D
conformal radiotherapy. Int J Radiat Oncol Biol Phys 35:1011-1018, 1996.
37. Pickett B, Vigneault E, Kurhanewicz J, et al: Static field intensity
modulation to treat a dominant intra-prostatic lesion to 90 Gy compared to seven
field 3-dimensional radiotherapy. Int J Radiat Oncol Biol Phys 44:921-929, 1999.
38. Zaider M, Zelefsky MJ, Lee EK, et al: Treatment planning for prostate
implants using magnetic-resonance spectroscopy imaging. Int J Radiat Oncol Biol
Phys 47:1085-1096, 2000.
39. Pickett B, Pirzkall J, Kurhanewicz J, et al: Radiosurgical intensity
modulated radiotherapy for prostate cancer (abstract 54). Int J Radiat Oncol
Biol Phys 48(3 suppl):138, 2000.
40. Vigneault E, Pouliot J, Laverdiere J, et al: Electronic portal imaging
device detection of radiopaque markers for evaluation of prostate position
during megavoltage irradiation: A clinical study. Int J Radiat Oncol Biol Phys
41. Chang JJ, Shinohara K, Bhargava V, et al: Prospective evaluation of
lateral biopsies of the peripheral zone for prostate cancer detection. J Urol
160(6 pt 1):2111-2114, 1998.
42. Terris MK: Sensitivity and specificity of sextant biopsies in the
detection of prostate cancer: Preliminary report. Urology 54(3):486-489, 1999.
43. Bauer JJ, Zeng J, Weir J, et al: Three-Dimensional computer-simulated
prostate models: Lateral prostate biopsies increase the detection rate of
prostate cancer. Urology 53(5):961-967, 1999.
44. Roach M, Pickett B, Rosenthal S, et al: Defining treatment margins for
3-D based six-field conformal (SFC) irradiation of localized prostate cancer.
Int J Radiat Oncol Biol Phys 28:267-275, 1994.
45. Xia P, Pickett B, Vigneault E, et al: Forward or inversely planned
segmental comparison of intensity modulated multileaf collinator/MRT and
sequential tomotherapy to treat multiple dominant intra-prostatic lesions of
prostate cancer to 90 Gy. Int J Radiat Oncol Biol Phys 51:224-254, 2001.
46. Shu H-KG, Vigneualt E, Weinberg V, et al: Toxicity following high
dose three-dimensional and intensity modulated radiation therapy for clinically
localized prostate cancer. Urol 57(1):102-107, 2001.
47. Speight JL, Weinberg VK, McLaughlin PW, et al: 3-D conformal radiotherapy
and higher than conventional doses improve PSA failure-free survival in
intermediate risk prostate carcinoma. Proceedings of the 41st Annual ASTRO
Meeting (abstract #2135) Int J Radiat Oncol Bio Phys 45(3) supplement, 1999.
48. Coakley FV, Hricak H: Radiologic anatomy of the prostate gland: A
clinical approach. Radiol Clin North Am 38:15-30, 2000.
49. Kurhanewicz J, Vigneron DB, Hricak H, et al: Prostate cancer: Metabolic
response to cryosurgery as detected with 3D H-1 MR spectroscopic imaging.
Radiology 200:489-496, 1996.
50. Parivar F, Hricak H, Shinohara K, et al: Detection of locally recurrent
prostate cancer after cryosurgery: Evaluation by transrectal ultrasound,
magnetic resonance imaging, and three-dimensional proton magnetic resonance
spectroscopy. Urology 48:594-599, 1996.
51. Parivar F, Kurhanewicz J: Detection of recurrent prostate cancer after
cryosurgery. Curr Opin Urol 8:83-86, 1998.