The Role of Magnetic Resonance in Prostate Cancer
Diagnosis, Characterization and Treatment
Natalia Kruchevsky
Submitted in partial fulfillment of the
requirements for the degree of
Masters of Arts
in the Graduate School of Arts and Sciences
Program in Biotechnology
Department of Biological Sciences
COLUMBIA UNIVERSITY
2013
© 2013
Natalia Kruchevsky
All Rights Reserved
ABSTRACT
The Role of Magnetic Resonance in Prostate Cancer Diagnosis, Characterization
and Treatment
Natalia Kruchevsky
One in six men will be affected by prostate cancer in their life time. Prostate cancer can
be slow or fast growing and it affects mainly men over fifty. Current options for
treatments are surgery, radiation, hormone therapy, immunotherapy, chemotherapy and
active surveillance. Magnetic resonance imaging and spectroscopy is a non-invasive,
sensitive, and non-radioactive way to detect, characterize and understand the anatomy,
physiology and metabolism of a tumor. MRI provides high image resolution that depicts
the zonal anatomy of the prostate and cancer in areas that may have been missed by a
biopsy. The field of MRI/MRS is constantly evolving toward new emerging techniques
that can provide higher accuracy and sensitivity for cancer detection as well as treatment
planning.
TABLE OF CONTENTS
List of Figures …………………………………………………………………..………..ii
Acknowledgements ……………………………………………………………………...iii
INTRODUCTION ………………………………………………………………………..1
The Prostate ………………………………………………………………………2
Magnetic Resonance: Prostate Imaging ………………………………….……………….4
Conventional MRI of the Prostate: The Endorectal MR Coil ..............................4
Magnetic resonance spectroscopic imaging ……….…………………….……..6
Dynamic contrast-enchanced MRI ………………....…………………………..8
Diffusion-weighted MRI …………...…………………………….……………..9
The role of MR in prostate cancer diagnosis …………………………………………....12
Diagnosis of prostate cancer …………………………..……………………....12
Tumor characterization ………………………………………………………..14
The role of MR in treatment planning for prostate cancer ……………………………....15
Surgery ……………………………………………………………………….15
Radiation therapy …………………………………………………………….16
Active surveillance …………………………………………………………...17
Detection of Recurrence of Disease …………………………………..…………………19
Future Directions ………………………………………………………………………..21
Exploring the use of MRI to decrease the number of biopsies ………………21
Hypoxia detection ……………………………………………………………21
PET/MRI ……………………………………………………………………..23
i
MR Image-guided Radiation Therapy (IGRT)……………..………………...24
Castration-resistant prostate cancer ………………...………………………..25
Conclusion ………………………………………………………………………………26
References ………………………………………………………………….……………27
ii
List of Figures
Figure 1: Zonal anatomy of prostate ······························································ 2
Figure 2: Axial endorectal MRI of prostate cancer in the peripheral zone ·················· 5
Figure 3: MRSI of a man with Stage 3 prostate cancer ········································· 7
Figure 4: DCE-MRI of prostate cancer …………………………………………..……….8
Figure 5: DWI of prostate cancer ………………………………………………....……..10
Figure 6: Signal to time curves from DCE-MRI · ………………………………………22
iii
Acknowledgements
I would like to thank my advisor, Dr. Ellen Ackerstaff for her enormous support,
guidance and constant feedback. I am extremely grateful for your help with this work,
and for teaching me everything I know about MRI research, my learning continues every
day. I am indebted for Dr. Jason Koutcher for his constant guidance throughout the years.
I also wish to thank Dr. Carol Lin for help throughout the program at Columbia
University and her feedback and review of this work.
This thesis is dedicated to my parents, Sofia and Michael Kruchevsky. Thank you for
always motivating, encouraging and believing in me. Everything I accomplished and will
accomplish in life is because of you.
iv
1
INTRODUCTION
Prostate cancer is the second leading cancer related cause of death in men
preceded only by lung cancer. It is estimated that in 2013 over two hundred thousand
people in United States will be diagnosed with prostate cancer with approximately thirty
thousand people will die from the disease (1). Prostate cancer is a disease associated with
age; 97% of all cases diagnosed are in men over fifty (1). The five year survival rate is
close to 100% if the disease is diagnosed in its early stages however the survival rate
drops to 28% if the disease is metastatic at time of diagnosis (1). The disease has a
higher prevalence in United States and Western Europe compared to Asia and South
Africa (1,2). In the US, African American men have a higher frequency of prostate
cancer than white men (1).
The major risk factors for prostate cancers are age, family history, and nutrition
(1). Genetic factors are responsible for 5-10% of all cancer cases diagnosed (3). Diets
rich in fat increase the chances of developing prostate cancer (1). Men with prostate
cancer usually experience problems with urination, such as frequent urination, blood in
the urine, inability to urinate or control urine flow, although these symptons are not
specific to prostate cancer (4). Treatment options include active surveillance, surgery,
radiation therapy, hormone therapy, chemotherapy and immunotherapy (1,5-7). Radiation
and surgery are potentially curative for patients with disease localized to the prostate.
Chemotherapy, hormone therapy, radiation and combinations of these are usually used to
treat people with advanced/metastatic prostate cancer. The optimal treatment is
determined based on several factors: age, stage, Gleason score (a measure of tumor
aggressiveness, and general health (1,8). Magnetic resonance imaging and spectroscopy
2
Figure 1: Zonal anatomy of the prostate. Abbreviations: CZ, central zone; TZ, transition zone; PZ,
peripheral zone. Reproduced with permission from (13).
serve an important role in the diagnosis, staging, and treatment planning of prostate
cancer.
The Prostate
The prostate gland is the size of a walnut and weights between 15-20 g in an
average young adult (9) and increases with age. The size of the prostate increases with
age and studies has shown that as BMI increases the size of the prostate increase for men
under 63 (10,11). The prostate is located below the bladder, anterior to the rectum, and it
surrounds the urethra, which carries urine as it leaves the bladder (Figure 1) (9,12,13).
The prostate secrets part of the seminal fluid (9). For older men, prostate cancer and
3
benign prostatic hyperplasia (BPH) are two major problems associated with the prostate
(9).
The prostate is divided into two parts: glandular and non-glandular areas (9).
The glandular area is further divided into inner and outer prostate: The inner prostate is
divided into transition zone (TZ) and periurethral glandular tissue. The outer prostate area
is separated into central (CZ) and peripheral zones (PZ). While PZ makes up seventy
percent of the glandular area, CZ and TZ account for twenty five and five percent
respectively of the prostate area (9,12). In an adult, the periurethral glandular tissue
accounts for less than one percent of the glandular area (14). The TZ which gives rise to
BPH consists of two tissue glands that engulf the two parts of the proximal urethra (14).
The CZ surrounds the ejaculatory ducts, the proximal urethra and the transition zone,
while the PZ encloses the CZ and the distal prostatic urethra (14). Seventy percent of all
prostate cancers originate from the PZ; 25% originate from the TZ and 5% from the CZ
(12).
4
Magnetic Resonance: Prostate Imaging
Magnetic resonance is a non invasive imaging tool that provides images of the
inside of the body. It uses a constant magnetic field and applies radio frequency waves to
measure changes in the net magnetization of protons (or other nuclei) in the body (15).
In the early 1970s, Raymond Damadian reported that MR can be used to distinguish
between cancerous and non cancerous tissue in vivo (16,17). In 1973, Paul Lauterbur
published the first 2D magnetic resonance image produced in a test tube (18). Four year
later in 1977, Damadian developed the first MRI machine and preformed the first wholebody image scan (19). In the same year, Peter Mansfield developed a novel mathematical
technique that reduced the scan time from hours to seconds (20). MRI uses a coil, one or
more loops of wire or copper foil to generate a radiofrequency field (15). Different coils
are used for different areas of the body and images are acquired in the axial, sagittal and
coronal planes (15). The entire procedure is harmless and does not include ionizing
radiation, as for example in computer tomography, or from radioactive compounds in
positron emission tomography (PET) (21-23). Magnetic resonance imaging techniques
include conventional MRI, MR spectroscopic imaging (MRSI), diffusion-weighted MRI
(DWI-MRI), and dynamic contrast-enhanced MRI (DCE-MRI).
Conventional MRI of the Prostate: The Endorectal MR Coil
An endorectal surface coil is placed in the rectum and is used to acquire a series of
images (24). The purpose of the endorectal coil is to allow detection of the signal as
close as possible to the tissue of interest (prostate) to maximize signal to noise. With
greater signal to noise, one can either shorten the acquisition time or obtain higher spatial
5
Figure 2: Endorectal MRI of prostate cancer in the Peripheral zone. (A) Axial T1 MR image does
not distinguish between the different areas of the prostate. (B) Axial T2 MR image: Low signal
intensity (*) indicates the cancer area. Reproduced with permission from (34).
resolution.
The wire/copper foil of the endorectal coil is covered with an inflatable
balloon, which is inflated with 60-80 ml of liquid perfluorocarbon or air before the scan
to lock the coil in its place (25,26). The endorectal MR coil provides a higher signal to
noise ratio during acquisition than an MR coil placed on or surrounding the abdomen,
since it is placed next to the prostate thus producing a better image quality of the prostate
(27). In addition, pelvic phased array MR coils are used to image the prostate and its
surrounding areas, slowly replacing endorectal MR coils for prostate imaging(24,28). The
combination of endorectal MRI and pelvic phase array coils provides currently the best
MR images for staging in prostate cancer (29). A magnet of at least 1.5 T or higher (3T,
new magnets of up-to 7T) is used to generate the best possible imaging (30). The images
acquired usually have a 3-4 mm slice thickness and 10-12 cm field of view (31). The
entire scan is roughly 40 minutes (25,28).
6
Two types of images are acquired: T1-weighted and T2-weighted spin echo
(24,31), with T1 referring to the longitudinal relaxation time and T2 to the transverse
relaxation time (32,33). These type of MR images are useful for tumor localization,
staging and detection (10). T2 MR images are acquired in the axial, coronal and sagittal
planes (30). On T1-weighted MR images, the prostate looks identical with the seminal
vesicles, thus lacking detailed anatomical information of the prostate (Figure 2a)
(24,31,34). On the other hand, T2-weighted MR images can distinguish between the
different areas of the prostate (Figure 2b) (24,31,34). Also on a T2-weighted MR image,
PZ has higher signal intensity than cancer tissue (24,31).
Magnetic resonance spectroscopic imaging
Magnetic resonance spectroscopic imaging (MRSI) is used to detect metabolites
in vivo (30,35). Different chemical groups can be distinguished in MRSI because they
have different absorption frequency depending on their environment and structure. As a
result, different nuclei, 1H,
13
C, and
31
P can be used to provide different information
about the molecules (35). During MRSI studies the concentration of various metabolites
can be measured. The current method uses three dimensional 1H MRSI with a volume
resolution, referred to as voxel, of 0.24 mm3 or smaller (30). An endorectal MR coil is
used to increase the signal to noise ratio and the entire scan lasts for about an hour
(30,35). The MRSI data are superimposed on T1- and T2-weighted MR images in order to
study the metabolic changes based on location in the prostate (Figure 3) (30,36). It is
important to suppress water and lipid signals during the 1H MRSI scan, since their signals
are typically much higher than other metabolite signals (35). Citrate (Cit), choline (Cho)
7
Figure 3: MRSI of a man with Stage 3 prostate cancer. (A) MRSI voxels of the central gland overlaid on
T2-weighted MR image. (B) Representative MRSI spectra of the voxels outlined in bold in (A), depicting
Choline, Citrate, and Creatine signals. MR images with overlaid metabolite images : Citrate (C) and
Choline (D), indicating that low citrate levels (green) correspond to high choline levels (purple) in prostate
cancer tissue. Adapted with permission from (36).
and creatine and polyamines (such as spermine, spermidine and putrescine)
concentrations can be identified from MRSI spectra (30,35,37). Their peaks resonate at
2.6, 3.2, 3.0, and 3.1 ppm representatively (26,35).
The levels of citrate change in different areas of the prostate and the levels do
not vary with age (36). However, choline levels remain unchanged through the prostate
(36). Normal prostate and BPH display a higher concentration of citrate than prostate
cancer tissue (Figure 3c) (35,36,38). Cancer cells have high concentration levels of
choline, which may be used as a marker to measure response to radiation therapy
(35,36,39). Moreover, cancer tissue have higher choline levels than BPH tissue thus, it
serves as a tool to differentiate cancerous and benign tissue (36). Changes in cell
8
Figure 4: DCE-MRI of prostate cancer. (A) Contrast-enhancement map overlayed on corresponding MR
image of the prostate using fast-field echo sequence (TR/TE, 17/2.9; flip angle, 15°). Axial contrastenhanced image shows abnormal regions are marked in red. (B) Representative average signal intensity-totime-curves. Regions of interest (ROI) 4 show a normal tissue enhancement. ROI 1 exhibits abnormal
enhancement with fast uptake and washout. (26).
functions due to cancer development affect the levels of citrate and choline in tissue (36).
The ratio (choline + creatine)/ citrate can be used to identify prostate cancer in patients
(36).
Dynamic contrast-enhanced MRI
Dynamic contrast-enhanced MRI (DCE-MRI) involves the intravenous injection
of
a
gadolinium
(Gd)
contrast
reagent
(26),
typically
Gd-DTPA
(Gd-
diethylenetriaminepentacetate). Images are acquired pre and post injection of the contrast
agent, permitting the visualization of tumor vascularity (40). The contrast agent passes
through the blood vessels in the body and enters the interstitial space of tissue in leaky
9
blood vessels, a characteristic of cancer tissue, until it is washed out from the body.
Signal enhancement is caused by the uptake of contrast agent in the tissue which causes
the water molecules to relax faster. Image enhancement is the result of vessel blood flow,
permeability of the blood vessel wall and composition of extracellular space (40).
There is a different in enhancement signals between cancer tumors compared to
normal tissue. (26). Prostate cancer shows early enhancement post Gd administration as
opposed to surrounding healthy tissue (40). Additionally, it is possible to differentiate
normal PZ, cancerous PZ tissue, stromal and glandular BPH (Figure 4) (26,41). Kim et al
showed that DCE-MRI is a more sensitive method for cancer detection in PZ and TZ
thanT2-weighted MR images, especially when acquired with parametric imaging and not
with an endorectal MR coil (42). DCE-MRI can also aid in detection
of cancers originating in the central gland (41).
Diffusion-weighted MRI
Diffusion-weighted imaging (DWI-MRI) measures the random motion of water
molecules (water diffusion) in tissues, and differences of the magnitude of water
diffusion can be used to detect and localize prostate cancer (43). Pure water diffuses
freely but in tissues, water diffuses more slowly. The extracellular water is limited in
diffusion by barriers such as cell membranes which limit how far the water molecules can
move without hitting a barrier. Higher cellular density, as often seen in tumors, is
associated with reduced extracellular space and thus, restricts water motion or diffusion.
10
Figure 5: DW-MRI of prostate cancer. (A) Axial T 2-weighted MR image, indicated prostate cancer
in the left lobe (* indicates the bladder) and (B) corresponding ADC map of the prostate
demonstrating low ADC values on the right tumor in the peripheral area (arrow). Adapted with
permission from (46).
However, high extracellular space and permeable cell membranes allow greater freedom
of movement of water especially between the intracellular and extracellular parts, (43).
The signal is acquired by measuring the movement of water inside the cell, outside the
cell and within the blood vessels. The motion of water is less restricted outside the cell
than within the cells. Areas with a higher cell density, such as the case with cancer, have
limited water motion thus they exhibit higher signal intensity, which appears bright on
the DW MR image (26,43). DWI-MRI allows one to determine apparent diffusion
coefficients (ADC), which is the measurement of water diffusion in a tissue (43). A map
of ADCs is generated by calculating the ADC values for each voxel on the MR image.
Low ADC values are a measure of restricted diffusion due to high cellular density, while
high ADC values usually are a sign that there is relatively free water diffusion, probably
11
caused by low cellular density (43). The images provide crucial information about tumor
localization in the prostate, as DW MR images of malignant PZ and TZ tissue display
lower ADC values than healthy PZ and TZ (Figure 5) (44-46).
12
The role of MR in prostate cancer diagnosis
Diagnosis of prostate cancer
Currently, the prostate specific antigen test (PSA) and digital rectal examination
(DRE) are used for prostate cancer screening. Men over 50 with a life expectancy of at
least ten years are recommended by the American Cancer Society to undergo routine
testing of PSA levels in the blood and DRE exam (1). The introduction of PSA tests in
1980’s allowed cancers to be diagnosed at a much earlier stage (24). PSA levels vary due
to inflammation or infection, and as result, many patients are being overtreated for
prostate cancer (47). Current recommendations by U.S. Preventive Services Task Force
do not support using the use of PSA screening (48). When an abnormal PSA and DRE
results suggest the presence of prostate cancer, transrectal ultrasound (TRUS)-guided
biopsy is used to confirm the presence of prostate cancer by histopathology of the biopsy
specimen(47). TRUS-guided biopsy was first introduced in 1968 as a means to detect
prostate volume and direct the needle to the right position (49). The original procedure
involved the removal of 6 samples from the prostate, now the method involves the
removal of 10 or more samples from different areas of the prostate to increase specificity
(47,50).
TRUS-guided biopsy possesses several problems for the accurate detection of
prostate cancer. First, negative biopsy results do not guarantee the absence of prostate
cancer. In fact 25-30% of men that undergo biopsy have a false negative result that
reveals prostate cancer in a second biopsy (51,52). Second, 25% of all prostate cancer
cases occur at the transition zone. Cancers in that area are small and are usually missed
13
in a biopsy due to lack of sampling (30,39,50). In addition, TRUS-guided biopsies often
undervalue the tumor volume (53).
The use of MRI has several benefits over TRUS-guided biopsies. First, MRI and
MRSI are able to detect cancers originating from the transition zone (30). The use of MRI
alone for tumor detection provides high specificity (77%), but low sensitivity (61%).
MRI/1H MRSI combination increases the specificity for cancer detection compared to
MRI alone (54). In addition, MRI has better accuracy for detecting cancer located at the
base and the middle of the prostate compared to TRUS-guided biopsy (53).
A new diagnostic tool, MRI-guided biopsy, was developed in order to improve the
diagnosis of prostate cancer. There are two types of MRI-guided biopsies, real-time MRIguided biopsy and Fusion MRI/US-guided biopsy (55-57). In real-time MRI-guided
biopsy, MR images are acquired to guide the insertion and the position of the needle
before sampling (57).
During MRI/US-guided biopsy, MRI is first acquired before the biopsy
procedure. The MR images are then used as a basis image set to guide the needle during
the US-guided biopsy procedure to the areas that appear suspicious on the MR scan (56).
The fusion method detects 9% more cancer per sample than TRUS-guided biopsy alone
and improves image quality (24,56). Additionally, this method allows for office-based
biopsies under local anesthesia, as demonstrated by Sonn et al. (55). Sonn et al. used a
device from Artemis that removes the need for general anesthesia during biopsy. The
device provides a map of the prostate biopsies; consequently, it is possible to determine
which area has not been sampled. Furthermore, the exact location of the biopsy in the
prostate is marked thus, if further biopsies are needed the procedure can be repeated at
14
the same location (55). Finally, MRI/US-guided biopsies are less expensive and time
consuming than real-time MRI-guided biopsies (55), although more costly than
ultrasound guided biopsies.
Tumor characterization
It is important to correctly characterize the tumor in order to determine the
optimal treatment. The Gleason score is used to characterize prostate cancer and it is one
of the factors that determine disease stage. Prostate cancer varies in its growth rate; it can
be fast or slow growing. Gleason score is a tool that measures the aggressiveness of
prostate cancer (8). After TRUS-guided biopsy, the samples are evaluated
histopathologically to determine their Gleason score. A grade, 1-5, is assigned to primary
and secondary tumor architecture. The two grades are added together to obtain the final
Gleason score between 2-10. A score of 6 or less indicates that the cancer is less
aggressive and has a low grade. A score of 8 indicates that the cancer is aggressive.
However, biopsy samples are not always accurate in predicting Gleason score due to
sampling error (58). Also, biopsy derived Gleason scores correlated to the Gleason score
from prostatectomy samples in only 31% of patients (59). Gleason score is
underestimated for 54% of patients by the biopsy although other report different
estimates ranging from 28 to 45 (59-63). 1H MRSI is a non-invasive way to assess tumor
aggressiveness (58). The Gleason score has been shown to correlate with (Cho+Cr)/Cit
ratio as determined from MRSI and increased tumor aggressiveness has been associated
with increased choline levels and decreased citrate levels (36,58,64).
15
The role of MR in treatment planning for prostate cancer
Surgery
Radical prostatectomy is a surgery to remove the entire prostate gland and
surrounding lymph nodes. The surgery can be performed in 2 different ways: invasive
(Radical retropubic prostatectomy and Radical perineal prostatectomy) and minimally
invasive (Laparoscopic radical prostatectomy and robotic-assisted laparoscopic
prostatectomy) (5). The treatment is most commonly performed at early stages of the
disease.
Preoperative endorectal MRI/MRSI can serve as a tool to validate and confirm
the surgeon’s decision regarding performing a nerve-sparing surgical technique and the
likelihood of successfully avoiding this complication during radical retropubic
prostatectomy (65).
The neurovascular bundles are located lateral to the prostate,
adjacent to the peripheral zone. Injury to the neurovascular bundle causes impotence and
loss of bowel and urinary continence. In high-risk patients, endorectal MRI changes the
surgical plan in 78% of the cases (65). High-risk patients are considered those who have
less than 25% probability that their tumor is confined to the prostate (65).
However, radical retropubic prostatectomy is associated with high-risk of
impotence and urinary incontinence (66). In addition, it is an invasive procedure that
requires hospital stay. Robotic-assisted laparoscopic prostatectomy (RALP) is less
invasive and has fewer side effects compared to open radical retropubic prostatectomy.
RALP allows the surgeon better visualization and control during the procedure. One
disadvantage is the loss of touch by the surgeon that is needed to establish and assess the
involvement of the neurovascular bundles with prostate cancer. According to McClure et
16
al., preoperative MRI changes the surgical plan in favor of a nerve sparing technique in
27% of all case studies (66).
Radiation therapy
Two types of radiation therapy are used to treat prostate cancer: brachytherapy
and external beam radiation therapy (6). In brachytherapy, small radioactive pellets are
placed inside the prostate. There are two types of brachytherapy: high dose rate (HDR)
and low dose rate (LDR). During LDR brachytherapy 70 to 150 seeds are implanted
directly into the prostate (67). The pellets are permanently implanted into the prostate
and give off radiation for weeks or months.
HDR brachytherapy is a temporary form of radiation treatment and provided
over three consecutive treatments. Catheters are placed inside the prostate then a
radioactive isotope, e.g. cesium (137Cs) or iridium (192Ir), are placed inside catheters for a
brief period of time. The treatment is performed three times over two days (6). The use
of MRI with brachytherapy planning allows selecting the correct amount of pellets to use
and determining the right placement of the catheter in HDR. Thus, the optimal dose of
radiation is achieved at the correct areas (68).
External beam radiation therapy (EBRT) is the second type of radiation therapy
available for patients (6). The treatment uses a machine to provide radiation to the
prostate gland. The treatment last between 7 to 9 weeks and is provided daily for 5 days
out of the week. CT scans are used to calculate the dose and location of radiation (69,70).
The target area, the prostate tumor, receives a high dose of radiation while the
surrounding area receives a small dose of radiation. On the CT scan it is hard to
17
distinguish the prostate from its surrounding areas. As mentioned earlier, MRI is better at
exhibiting the anatomy and the boundaries of the prostate, i.e. provides soft tissue
contrast not available on CT. Thus, it provides better target treatment planning than a CT
scan (ref). Furthermore, MRI can be used to calculate the dose of radiation as accurately
as CT scans (70). In addition, MRI is superior to CT since it prevents unnecessary
exposure to radiation (70).
Active surveillance
The number of new cases of prostate cancer diagnoses annually increased
drastically since implementation of PSA testing (1). The increase in new cases also
results in higher number of people diagnosed with locally, low risk prostate cancer (7,24).
However, with the increase in the number of people diagnosed at early stages, there is a
concern for overtreatment of patients (7,47). Active surveillance (AS) is used to monitor
disease progression and to help decide when to treat with a goal of treating only when
tests indicate that the cancer is growing. The tumor must be less than a 0.5 cm3 in volume
with a Gleason score of 6 or less and located only in the prostate in order for a patient to
be considered for active surveillance (7). Every six months, patients undergo a PSA and
DRE tests and every year a biopsy to determine the progression of the disease (7). Active
surveillance allows people to avoid the side effects associated with treatment and have a
better quality of life (7).
One of the problems associated with active surveillance is missing high-grade
cancers with a TRUS-guided biopsy. As a result, a second biopsy is conducted before
beginning active surveillance to confirm the Gleason score (71). A recent study by
18
Vergas et al. concluded that patients with non-visible tumor on an MRI scan have low
grade results on their second biopsy. On the other hand, patients that have visible tumor
on their MRI scan have a higher change that their disease status might be upgraded after
the second biopsy. Thus, endorectal MRI can help selecting patients for AS (71).
Moreover, Turkbey et al. conducted a study between 2007 and 2010 with 133 patients to
evaluate the use of multiparametric MR in identifying candidates for AS (72). They
concluded that multiparametic MR with a specificity of 93% and sensitivity of 92% is a
better and more sensitive diagnostic tool for selecting patients for AS than the current
tools used.
19
Detection of Recurrent Disease
In order to provide better treatment methods for patients with prostate cancer, it is
important to detect tumor recurrence early on after treatment with EBRT and radical
prostatectomy (73-75). Post radical prostatectomy, a measurable PSA is a sign of residual
or recurrent disease. A strict cutoff post radiation is not available but PSA’s greater than
one are usually of concern (73,76). This will lead to restaging looking for distant disease.
If this is negative, a TRUS guided biopsy is performed. As previously stated biopsy is an
invasive procedure and results are not always accurate. Approximately one third of the
patients have to have several biopsies in order to confirm recurrence (73). Here, MRI can
serve as a more accurate tool to determine recurrence (73-75).
DCE-MRI can also be used to evaluate local recurrence after radical
prostatectomy (73). Tumor recurrences show early enhancement after intravenous
injection of the contrast reagent then they reach a plateau or wash out. On the other hand,
benign areas show early enhancement in less than half the cases. Furthermore, DCE-MRI
increases the accuracy of detection by 33% and sensitivity by 56% compared to DRE
exams (73).
In addition, MRSI can be used to evaluate local recurrence after EBRT (74).
One benefit of MRSI is that it evaluates metabolite changes rather than anatomic
changes. Following treatment with EBRT, the prostate has undergone anatomic changes
that are hard to distinguish with conventional MRI and TRUS methods. Studies have
shown that after radiation treatment citrate and choline levels are usually undetectable
(77). As a result, the (cho +cr)/cit ratio, which is used to evaluate untreated patients,
cannot be used. Instead, Coakley et al. compared choline levels to creatine, if levels are
20
detectable during the scan, otherwise choline is compared to the noise levels (74). MRSI
has a sensitivity of 78%, while biopsy and DRE exhibit sensitivity of 48% and 16%,
respectively (75).
21
Future Directions
Exploring the use of MRI to decrease the number of biopsies
The prostate MR imaging study, PROMIS, trial is currently being conducted in
the UK (78). The trial seeks to evaluate if MRI can decrease the number of unnecessary
biopsies and improve the quality of the biopsies performed. Abnormal PSA results
suggest the presence of prostate cancer, a speculation which is further evaluated by
biopsy (47). However, many factors, such as inflammation or infection, can cause high
PSA levels. In fact PSA levels vary day to day between people (47). As a result, some
men will undergo unneeded biopsies, which result in a negative outcome. Participants of
the PROMIS trial first undergo an initial MRI, a combined biopsy procedure (template
prostate mapping (TPM) biopsy and a TRUS biopsy) as soon as possible after the MRI
scan (78). All results are evaluated separately in order to avoid predisposition. The trial
will end in 2015. The results can serve as a valuable tool in preventing unnecessary
biopsies and increasing the accuracy of diagnosis.
Hypoxia detection
One of the main characteristics of tumors is hypoxia, i.e. low oxygen
concentration in selected tumor areas. Advanced cancers are associated with increased
numbers and size of hypoxic areas (79). Tumor blood vessels have functional
abnormalities, resulting in poorly-perfused tumor areas, and thus providing inadequate
oxygen supply to the tumor cells(79). Hypoxic tumors are two to three times more
resistant to radiotherapy than non hypoxic tumors and are often associated with more
aggressive
22
Figure 6: Average Signal to time curves from DCE-MRI representing three different significant contrast
agent uptake patterns for (A) a rat prostate tumor model and (B) a prostate tumor from a patient. In (A), the
green curve depicts a pattern representative of contrast uptake behavior in hypoxic areas, while the blue and
red uptake curves depict the patterns characterizing the necrotic and perfused areas respectively. Adapted
with permission from (81). In (B), the top curve pattern is similar to the red curve (A) observed for the
preclinical prostate cancer model, while the 2nd and the 3rd pattern are similar to the green and blue curve in
(A), respectively. These patterns indicate that similar microenvironments – i.e. well-perfused, hypoxic, and
necrotic areas – to preclinical tumor models may be present and identified by DCE-MRI in human prostate
tumors. (C) Spatial, weighted distributions of the different uptake patterns depicted in (B) across the tumor.
White to bright yellow – pixel consist of predominantly one contrast uptake pattern, correspondingly the
other uptake pattern depict black or dark red, while shades in between depict contributions of more than one
pattern to a voxel. Adapted with permission from (82).
tumor types (79,80). Hypoxia also increases gene instability by promoting gene mutation
and amplification, resistance to apoptosis (80).
In order to provide better treatment planning, it is important to know the
distribution of hypoxia in the tumor. DCE-MRI can provide valuable information about
tumor perfusion and blood vessel structure (40). Using preclinical DCE-MRI, PET, and
immunohistochemical data, an unsupervised pattern recognition (PR) technique was
developed by Stoyanova et al. to identify areas in the tumor that are hypoxic using alone
the signal to time curves from DCE-MRI data (81). The signal versus time curves exhibit
specific shapes that corresponds to necrotic, hypoxic and well-perfused areas in a
preclinical prostate tumor model (Figure 6 A). Hypoxic areas have slow uptake and
23
washout of Gd-DTPa in DCE-MRI, while areas with adequate oxygen supply exhibit
rapid Gd-DTPA uptake and washout and, necrotic areas have no Gd-DTPa uptake at all
or slowly increasing Gd-DTPA uptake (81). The shape of the curves and their tumoral
location indicate the vascularity of the tumor. A pattern map represents the prevalence
(weight) of a signal-to-time curve pattern for each pixel (voxel) (Figure 6c) (81,82). As
the PR method takes into account both the uptake and the washout of the contrast reagent
and uses a pattern rather than a single-voxel uptake curve, small differences in
enhancement due to tumor hypoxia can be distinguished from enhancement characteristic
for well-perfused/vascularized areas (Figure 6a) (81). Preliminary patient studies have
identified similar patterns in clinical DCE-MRI data from a prostate tumor (Figure 6B),
and their corresponding spatial distributions (pattern maps) are shown in Figure 6C (82).
The similarity between the pre-clinical model and the clinical data implies that the
method might have an application for patient use.
PET/MRI
In the mid 1990’s Shao and Cherry et al. developed a pre-clinical prototype that
acquires PET and MRI images simultaneously (83). Soon after pre-clinical and clinical
PET/MR scanner were developed by Philips and Siemens (84). In 2011, the FDA
approved the first clinical PET/MRI developed by Siemens (85). Positron emission
tomography (PET) works by detecting two gamma rays produced by the emission of a
positron from the nucleus of the radioactive isotope in the tracer. It uses the radioactive
glucose analog tracer 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (18F-FDG) to generate 3dimensional images of the tracer location in the body (86). FDG is transported by the
24
glucose receptors into the cell where it is phosphorylated to FDG-6-phosphate by
hexokinase. The main difference between the tracer and glucose is that FDG has
hydrogen instead of a hydroxyl group at its second carbon, in addition to the fluorine
radioactive label. As a result, glycolysis cannot continue with FDG-6-P and the FDG
accumulates in the cells (86). Cancer tissue have high accumulation of FDG in the cells
since they are characterized by typically high aerobic glycolysis contrary to noncancerous cells, a phenomenon known as the Warburg effect (87-89). Thus, PET
provides information for the diagnosis and staging of cancer (86).
Combining PET/MRI into one procedure provides several benefits. First, the
images are acquired at the same time, the patient is not moved from one machine to
another, and thus the same position is maintained throughout the scan. As a result, PET
and MR images are already aligned with each other and spatial information from the two
different methods can be compared more accurately. Second, PET/MRI uses a lower dose
of radiation than similar hybrid scanner, PET/CT, as MRI does not expose the patient to
any ionizing radiation. Finally, the new hybrid is more time efficient, since instead of two
scans patients have to undergo only one scan (84).
The new scanner has already shown promising results in brain, melanoma, chest,
and bone cancer (22,23). Wetter et al. conducted the first clinical trial using PET/MRI for
patients with prostate cancer. The group concluded despite promising results, further
studies have be conducted to determine the effect on prostate cancer staging and
diagnosis (90).
MR Image-guided Radiation Therapy (IGRT)
25
A new type of technology developed by ViewRay, Inc. that received 510(k) pre
market approval by the FDA, may provide better treatment option for people with cancer
(91). The device deliveries radiation therapy and simultaneously acquires MR images.
The system allows predicting the dose of treatment based on images captured during the
scan. Furthermore, the scanner permits adaptation for movement that might occur (91).
Now radiologists can see where radiation is being delivered and record continuous soft
tissue imaging, which is a major benefit. Presently, CT or X-rays are used to determine
the location of radiation therapy before the start of treatment. However, this process adds
unnecessary radiation exposure to the patient. Similar to other techniques already
discussed, patients are exposed to a smaller amount of radiation with the new scanner
(92). The Siteman Cancer Center at Barnes Jewish and Washington University conducted
a clinical trial consisting of 27 patients with lung, head and neck, prostate and breast
cancer, though the results of the study have not been published yet (93).
Castration- resistant prostate cancer
Castration-resistant prostate cancer (CRPC) is a type of advanced cancer that grows
despite surgical or androgen hormone deprivation treatments (94). Only 10-20% of
people with prostate cancer will develop CRPC. The prognosis for people with CRPC is
poor with a mean overall survival between 9 to 30 months and treatment remains a
challenge (94). Of the patients with metastatic prostate cancer, 90% will develop
metastasis in the bone (95). Furthermore, results of one study indicate that a third of
patients with CRPC develop bone metastases within two years of diagnosis (94).
26
MRI can detect bone metastases and also to predict treatment response. Dahut
et al. used DCE- MRI of the prostate to evaluate patient outcome to treatment with
cediranib, a daily angiogenesis drug (96). DCE-MRI measurements were collected less
than seven days before starting treatment, then a day after treatment. Additional DCEMRI scans were collected 4 and 8 weeks after start of treatment. The scans revealed a
positive response to treatment and demonstrated the power of DCE-MRI to assess the
treatment response. Using MRI, the University of Chicago is currently conducting a
clinical trial to evaluate the response to cabozantinib, an angiogenesis drug, in bone
metastases in prostate cancer patients (97). Further research is needed in order to help
identify CRPC earlier and provide better treatment methods.
27
Conclusion
One in six men in their life time will be diagnosed with prostate cancer. The
disease has high five year survival rates; however, improvements in diagnostic and
treatment methods are necessary. MRI/1H MRSI serves as an important tool in the
diagnosis, staging, treatment, and detection of recurrence of this disease. It has greatly
evolved and improved since the first MR scan thirty years ago. The combination of
MRI/1H MRSI greatly improves diagnosis by accurately determining the volume, stage
and location of a tumor. In the future, magnetic resonance may be able to provide much
more sensitive and accurate detection and characterization of cancer using PET/MRI and
other MRI scans before conducting biopsies. Treatment options may perhaps greatly
improve once hypoxic areas are better detected and evaluated. Finally, treatment
accuracy can increase with the use of MR guided therapy.
28
References:
1.
American Cancer Society. Cancer Facts & Figures 2013.
2.
Fair, W. R., Fleshner, N. E. & Heston, W.(1997) Cancer of the prostate: a
nutritional disease? Urology 50, 840-848.
3.
Bratt, O.(2002) Hereditary prostate cancer: clinical aspects. J Urol 168, 906-913.
4.
Society, A. C. (2012). What are the signs and symptoms of prostate cancer?,
Accessed
on
5/6/2013.
<http://www.cancer.org/cancer/prostatecancer/moreinformation/prostatecancerear
lydetection/prostate-cancer-early-detection-symptoms-of-prostate-cancer>.
5.
Encyclopedia, A. D. A. M. M. (2012). Radical prostatectomy, Accessed on
03/10/2013. <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0004554/>.
6.
cancer.org. (2013). Radiation therapy for prostate cancer, Accessed on
03/10/2013. <http://www.cancer.org/cancer/prostatecancer/detailedguide/prostatecancer-treating-radiation-therapy>.
7.
Tosoian, J. J., Trock, B. J., Landis, P., Feng, Z., Epstein, J. I., Partin, A. W.,
Walsh, P. C. & Carter, H. B.(2011) Active surveillance program for prostate
cancer: an update of the Johns Hopkins experience. J Clin Oncol 29, 2185-2190.
8.
Gleason, D. F. & Mellinger, G. T.(1974) Prediction of prognosis for prostatic
adenocarcinoma by combined histological grading and clinical staging. J Urol
111, 58-64.
9.
Coakley, F. V. & Hricak, H.(2000) Radiologic anatomy of the prostate gland: a
clinical approach. Radiol Clin North Am 38, 15-30.
10.
Allen, K. S., Kressel, H. Y., Arger, P. H. & Pollack, H. M.(1989) Age-related
changes of the prostate: evaluation by MR imaging. AJR Am J Roentgenol 152,
77-81.
11.
Freedland, S. J., Platz, E. A., Presti, J. C., Jr., Aronson, W. J., Amling, C. L.,
Kane, C. J. & Terris, M. K.(2006) Obesity, serum prostate specific antigen and
prostate size: implications for prostate cancer detection. J Urol 175, 500-504;
discussion 504.
12.
Lee, C. H., Akin-Olugbade, O. & Kirschenbaum, A.(2011) Overview of prostate
anatomy, histology, and pathology. Endocrinol Metab Clin North Am 40, 565575, viii-ix.
13.
Zhai, L., Madden, J., Foo, W. C., Palmeri, M. L., Mouraviev, V., Polascik, T. J. &
Nightingale, K. R.(2010) Acoustic radiation force impulse imaging of human
prostates ex vivo. Ultrasound Med Biol 36, 576-588.
29
14.
McNeal, J. E.(1981) The zonal anatomy of the prostate. Prostate 2, 35-49.
15.
Storey, P.(2006) Introduction to magnetic resonance imaging and spectroscopy.
Methods Mol Med 124, 3-57.
16.
Damadian, R.(1971) Tumor detection by nuclear magnetic resonance. Science
171, 1151-1153.
17.
Damadian, R., Zaner, K., Hor, D. & DiMaio, T.(1974) Human tumors detected by
nuclear magnetic resonance. Proc Natl Acad Sci U S A 71, 1471-1473.
18.
Lauterbur, P. C.(1989) Image formation by induced local interactions. Examples
employing nuclear magnetic resonance. 1973. Clin Orthop Relat Res, 3-6.
19.
Technology, M. I. o. 2001 Lemelson-MIT Lifetime Achievement Award Winner,
Accessed
on
03/01/2012.
<http://web.mit.edu/invent/a-winners/adamadian.html>.
20.
P, M.(1977) Multi-planar image formation using NMR spin echoes. Journal of
physics. C, Solid state physics 10, L55-L58.
21.
Hricak, H., Dooms, G. C., McNeal, J. E., Mark, A. S., Marotti, M., Avallone, A.,
Pelzer, M., Proctor, E. C. & Tanagho, E. A.(1987) MR imaging of the prostate
gland: normal anatomy. AJR Am J Roentgenol 148, 51-58.
22.
Buchbender, C., Heusner, T. A., Lauenstein, T. C., Bockisch, A. & Antoch,
G.(2012) Oncologic PET/MRI, part 1: tumors of the brain, head and neck, chest,
abdomen, and pelvis. J Nucl Med 53, 928-938.
23.
Buchbender, C., Heusner, T. A., Lauenstein, T. C., Bockisch, A. & Antoch,
G.(2012) Oncologic PET/MRI, part 2: bone tumors, soft-tissue tumors,
melanoma, and lymphoma. J Nucl Med 53, 1244-1252.
24.
Purohit, R. S., Shinohara, K., Meng, M. V. & Carroll, P. R.(2003) Imaging
clinically localized prostate cancer. Urol Clin North Am 30, 279-293.
25.
Cancer, Z. T. E. o. P. (2011). Magnetic Resonance Imaging (MRI), Accessed on
02/27/2013. <http://zerocancer.org/education/testing/MRI/>.
26.
Verma, S. & Rajesh, A.(2011) A clinically relevant approach to imaging prostate
cancer: review. AJR Am J Roentgenol 196, S1-10 Quiz S11-14.
27.
Martin, J. F., Hajek, P., Baker, L., Gylys-Morin, V., Fitzmorris-Glass, R. &
Mattrey, R. R.(1988) Inflatable surface coil for MR imaging of the prostate.
Radiology 167, 268-270.
28.
ProstateMRI.com. (Unknown). Prostate Cancer Diagnosis and Staging, Accessed
on 02/27/2013. <http://prostatemri.com/mdiagnosis.html>.
30
29.
Hricak, H., White, S., Vigneron, D., Kurhanewicz, J., Kosco, A., Levin, D.,
Weiss, J., Narayan, P. & Carroll, P. R.(1994) Carcinoma of the prostate gland:
MR imaging with pelvic phased-array coils versus integrated endorectal--pelvic
phased-array coils. Radiology 193, 703-709.
30.
Hricak, H.(2005) MR imaging and MR spectroscopic imaging in the pretreatment evaluation of prostate cancer. Br J Radiol 78 Spec No 2, S103-111.
31.
Schnall, M. D. & Pollack, H. M.(1990) Magnetic resonance imaging of the
prostate gland. Urol Radiol 12, 109-114.
32.
P., H. J.
33.
Felix, B.(1946) Nuclear Induction. Physical review 70, 460.
34.
Gupta, E. & Torigian, D. A.(2009) MR Imaging of the Prostate Gland, PET
Clinics. PET Clin 4, 139-155.
35.
Koutcher, J. A., Zakian, K. & Hricak, H.(2000) Magnetic resonance spectroscopic
studies of the prostate. Mol Urol 4, 143-152;discussion 153.
36.
Kurhanewicz, J., Vigneron, D. B., Hricak, H., Narayan, P., Carroll, P. & Nelson,
S. J.(1996) Three-dimensional H-1 MR spectroscopic imaging of the in situ
human prostate with high (0.24-0.7-cm3) spatial resolution. Radiology 198, 795805.
37.
Swanson, M. G., Zektzer, A. S., Tabatabai, Z. L., Simko, J., Jarso, S., Keshari, K.
R., Schmitt, L., Carroll, P. R., Shinohara, K., Vigneron, D. B. & Kurhanewicz,
J.(2006) Quantitative analysis of prostate metabolites using 1H HR-MAS
spectroscopy. Magn Reson Med 55, 1257-1264.
38.
Zakian, K. L., Shukla-Dave, A., Ackerstaff, E., Hricak, H. & Koutcher, J.
A.(2008) 1H magnetic resonance spectroscopy of prostate cancer: biomarkers for
tumor characterization. Cancer Biomark 4, 263-276.
39.
Zakian, K. L., Eberhardt, S., Hricak, H., Shukla-Dave, A., Kleinman, S.,
Muruganandham, M., Sircar, K., Kattan, M. W., Reuter, V. E., Scardino, P. T. &
Koutcher, J. A.(2003) Transition zone prostate cancer: metabolic characteristics at
1H MR spectroscopic imaging--initial results. Radiology 229, 241-247.
40.
Barentsz, J. O., Engelbrecht, M., Jager, G. J., Witjes, J. A., de LaRosette, J., van
Der Sanden, B. P., Huisman, H. J. & Heerschap, A.(1999) Fast dynamic
gadolinium-enhanced MR imaging of urinary bladder and prostate cancer. J Magn
Reson Imaging 10, 295-304.
41.
Noworolski, S. M., Henry, R. G., Vigneron, D. B. & Kurhanewicz, J.(2005)
Dynamic contrast-enhanced MRI in normal and abnormal prostate tissues as
defined by biopsy, MRI, and 3D MRSI. Magn Reson Med 53, 249-255.
(2011).
31
42.
Kim, J. K., Hong, S. S., Choi, Y. J., Park, S. H., Ahn, H., Kim, C. S. & Cho, K.
S.(2005) Wash-in rate on the basis of dynamic contrast-enhanced MRI: usefulness
for prostate cancer detection and localization. J Magn Reson Imaging 22, 639646.
43.
Koh, D. M. & Collins, D. J.(2007) Diffusion-weighted MRI in the body:
applications and challenges in oncology. AJR Am J Roentgenol 188, 1622-1635.
44.
Issa, B.(2002) In vivo measurement of the apparent diffusion coefficient in
normal and malignant prostatic tissues using echo-planar imaging. J Magn Reson
Imaging 16, 196-200.
45.
Sato, C., Naganawa, S., Nakamura, T., Kumada, H., Miura, S., Takizawa, O. &
Ishigaki, T.(2005) Differentiation of noncancerous tissue and cancer lesions by
apparent diffusion coefficient values in transition and peripheral zones of the
prostate. J Magn Reson Imaging 21, 258-262.
46.
Giannarini, G., Petralia, G. & Thoeny, H. C.(2012) Potential and limitations of
diffusion-weighted magnetic resonance imaging in kidney, prostate, and bladder
cancer including pelvic lymph node staging: a critical analysis of the literature.
Eur Urol 61, 326-340.
47.
Pinthus, J. H., Pacik, D. & Ramon, J.(2007) Diagnosis of prostate cancer. Recent
Results Cancer Res 175, 83-99.
48.
Force, U. S. P. S. T. (2012). Screening for Prostate Cancer, Accessed on
04/11/2012.
<http://www.uspreventiveservicestaskforce.org/prostatecancerscreening/prostatefi
nalrs.htm>.
49.
Dahnert, W. F., Hamper, U. M., Eggleston, J. C., Walsh, P. C. & Sanders, R.
C.(1986) Prostatic evaluation by transrectal sonography with histopathologic
correlation: the echopenic appearance of early carcinoma. Radiology 158, 97-102.
50.
Taneja, S. S.(2006) Prostate biopsy: targeting cancer for detection and therapy.
Rev Urol 8, 173-182.
51.
Roehl, K. A., Antenor, J. A. & Catalona, W. J.(2002) Serial biopsy results in
prostate cancer screening study. J Urol 167, 2435-2439.
52.
Graif, T., Loeb, S., Roehl, K. A., Gashti, S. N., Griffin, C., Yu, X. & Catalona, W.
J.(2007) Under diagnosis and over diagnosis of prostate cancer. J Urol 178, 88-92.
53.
Mullerad, M., Hricak, H., Kuroiwa, K., Pucar, D., Chen, H. N., Kattan, M. W. &
Scardino, P. T.(2005) Comparison of endorectal magnetic resonance imaging,
guided prostate biopsy and digital rectal examination in the preoperative
anatomical localization of prostate cancer. J Urol 174, 2158-2163.
32
54.
Scheidler, J., Hricak, H., Vigneron, D. B., Yu, K. K., Sokolov, D. L., Huang, L.
R., Zaloudek, C. J., Nelson, S. J., Carroll, P. R. & Kurhanewicz, J.(1999) Prostate
cancer: localization with three-dimensional proton MR spectroscopic imaging-clinicopathologic study. Radiology 213, 473-480.
55.
Sonn, G. A., Natarajan, S., Margolis, D. J., MacAiran, M., Lieu, P., Huang, J.,
Dorey, F. J. & Marks, L. S.(2013) Targeted biopsy in the detection of prostate
cancer using an office based magnetic resonance ultrasound fusion device. J Urol
189, 86-91.
56.
Pinto, P. A., Chung, P. H., Rastinehad, A. R., Baccala, A. A., Jr., Kruecker, J.,
Benjamin, C. J., Xu, S., Yan, P., Kadoury, S., Chua, C., Locklin, J. K., Turkbey,
B., Shih, J. H., Gates, S. P., Buckner, C., Bratslavsky, G., Linehan, W. M.,
Glossop, N. D., Choyke, P. L. & Wood, B. J.(2011) Magnetic resonance
imaging/ultrasound fusion guided prostate biopsy improves cancer detection
following transrectal ultrasound biopsy and correlates with multiparametric
magnetic resonance imaging. J Urol 186, 1281-1285.
57.
Anastasiadis, A. G., Lichy, M. P., Nagele, U., Kuczyk, M. A., Merseburger, A. S.,
Hennenlotter, J., Corvin, S., Sievert, K. D., Claussen, C. D., Stenzl, A. &
Schlemmer, H. P.(2006) MRI-guided biopsy of the prostate increases diagnostic
performance in men with elevated or increasing PSA levels after previous
negative TRUS biopsies. Eur Urol 50, 738-748; discussion 748-739.
58.
Zakian, K. L., Sircar, K., Hricak, H., Chen, H. N., Shukla-Dave, A., Eberhardt, S.,
Muruganandham, M., Ebora, L., Kattan, M. W., Reuter, V. E., Scardino, P. T. &
Koutcher, J. A.(2005) Correlation of proton MR spectroscopic imaging with
gleason score based on step-section pathologic analysis after radical
prostatectomy. Radiology 234, 804-814.
59.
Cookson, M. S., Fleshner, N. E., Soloway, S. M. & Fair, W. R.(1997) Correlation
between Gleason score of needle biopsy and radical prostatectomy specimen:
accuracy and clinical implications. J Urol 157, 559-562.
60.
Kim, K. H., Lim, S. K., Shin, T. Y., Lee, J. Y., Chung, B. H., Rha, K. H. & Hong,
S. J.(2013) Upgrading of Gleason score and prostate volume: a
clinicopathological analysis. BJU Int
61.
Lattouf, J. B. & Saad, F.(2002) Gleason score on biopsy: is it reliable for
predicting the final grade on pathology? BJU Int 90, 694-698; discussion 698699.
62.
Corcoran, N. M., Hong, M. K., Casey, R. G., Hurtado-Coll, A., Peters, J.,
Harewood, L., Goldenberg, S. L., Hovens, C. M., Costello, A. J. & Gleave, M.
E.(2011) Upgrade in Gleason score between prostate biopsies and pathology
following radical prostatectomy significantly impacts upon the risk of
biochemical recurrence. BJU Int 108, E202-210.
33
63.
Tavangar, S. M., Razi, A. & Mashayekhi, R.(2004) Correlation between prostate
needle biopsy and radical prostatectomy Gleason gradings of 111 cases with
prostatic adenocarcinoma. Urol J 1, 246-249.
64.
B., V. D., Ryan, M., Susan, N., J., N. S., Juergen, S., Dahlia, S., Hedvig, H., Peter,
C. & John, K. in ISMRM 6th Annual Mtg.
65.
Hricak, H., Wang, L., Wei, D. C., Coakley, F. V., Akin, O., Reuter, V. E., Gonen,
M., Kattan, M. W., Onyebuchi, C. N. & Scardino, P. T.(2004) The role of
preoperative endorectal magnetic resonance imaging in the decision regarding
whether to preserve or resect neurovascular bundles during radical retropubic
prostatectomy. Cancer 100, 2655-2663.
66.
McClure, T. D., Margolis, D. J., Reiter, R. E., Sayre, J. W., Thomas, M. A.,
Nagarajan, R., Gulati, M. & Raman, S. S.(2012) Use of MR imaging to determine
preservation of the neurovascular bundles at robotic-assisted laparoscopic
prostatectomy. Radiology 262, 874-883.
67.
Services, P. H. (2013). LDR brachytherapy, Accessed on 05/05/2013.
<http://oregon.providence.org/patients/healthconditionscare/ldrbrachytherapy/Pages/default.aspx>.
68.
D'Amico, A. V., Cormack, R., Tempany, C. M., Kumar, S., Topulos, G., Kooy,
H. M. & Coleman, C. N.(1998) Real-time magnetic resonance image-guided
interstitial brachytherapy in the treatment of select patients with clinically
localized prostate cancer. Int J Radiat Oncol Biol Phys 42, 507-515.
69.
Villeirs, G. M. & De Meerleer, G. O.(2007) Magnetic resonance imaging (MRI)
anatomy of the prostate and application of MRI in radiotherapy planning. Eur J
Radiol 63, 361-368.
70.
Kapanen, M., Collan, J., Beule, A., Seppala, T., Saarilahti, K. & Tenhunen,
M.(2012) Commissioning of MRI-only based treatment planning procedure for
external beam radiotherapy of prostate. Magn Reson Med
71.
Vargas, H. A., Akin, O., Afaq, A., Goldman, D., Zheng, J., Moskowitz, C. S.,
Shukla-Dave, A., Eastham, J., Scardino, P. & Hricak, H.(2012) Magnetic
resonance imaging for predicting prostate biopsy findings in patients considered
for active surveillance of clinically low risk prostate cancer. J Urol 188, 17321738.
72.
Turkbey, B., Mani, H., Aras, O., Ho, J., Hoang, A., Rastinehad, A. R., Agarwal,
H., Shah, V., Bernardo, M., Pang, Y., Daar, D., McKinney, Y. L., Linehan, W.
M., Kaushal, A., Merino, M. J., Wood, B. J., Pinto, P. A. & Choyke, P. L.(2013)
Prostate Cancer: Can Multiparametric MR Imaging Help Identify Patients Who
Are Candidates for Active Surveillance? Radiology
34
73.
Casciani, E., Polettini, E., Carmenini, E., Floriani, I., Masselli, G., Bertini, L. &
Gualdi, G. F.(2008) Endorectal and dynamic contrast-enhanced MRI for detection
of local recurrence after radical prostatectomy. AJR Am J Roentgenol 190, 11871192.
74.
Coakley, F. V., Teh, H. S., Qayyum, A., Swanson, M. G., Lu, Y., Roach, M., 3rd,
Pickett, B., Shinohara, K., Vigneron, D. B. & Kurhanewicz, J.(2004) Endorectal
MR imaging and MR spectroscopic imaging for locally recurrent prostate cancer
after external beam radiation therapy: preliminary experience. Radiology 233,
441-448.
75.
Pucar, D., Shukla-Dave, A., Hricak, H., Moskowitz, C. S., Kuroiwa, K., Olgac,
S., Ebora, L. E., Scardino, P. T., Koutcher, J. A. & Zakian, K. L.(2005) Prostate
cancer: correlation of MR imaging and MR spectroscopy with pathologic findings
after radiation therapy-initial experience. Radiology 236, 545-553.
76.
Foundation, P. C. PSA Rising Post-Treatment, Accessed on 05/07/2013.
<http://www.pcf.org/site/c.leJRIROrEpH/b.5838551/k.6D69/PSA_Rising_PostTr
eatment.htm>.
77.
Mueller-Lisse, U. G., Swanson, M. G., Vigneron, D. B., Hricak, H., Bessette, A.,
Males, R. G., Wood, P. J., Noworolski, S., Nelson, S. J., Barken, I., Carroll, P. R.
& Kurhanewicz, J.(2001) Time-dependent effects of hormone-deprivation therapy
on prostate metabolism as detected by combined magnetic resonance imaging and
3D magnetic resonance spectroscopic imaging. Magn Reson Med 46, 49-57.
78.
Unit, M. C. T. (2013). MRC Study Details, Accessed on 01/20/2013.
<http://www.ctu.mrc.ac.uk/research_areas/study_details.aspx?s=126#0>.
79.
Vaupel, P.(2004) Tumor microenvironmental physiology and its implications for
radiation oncology. Semin Radiat Oncol 14, 198-206.
80.
Varlotto, J. & Stevenson, M. A.(2005) Anemia, tumor hypoxemia, and the cancer
patient. Int J Radiat Oncol Biol Phys 63, 25-36.
81.
Stoyanova, R., Huang, K., Sandler, K., Cho, H., Carlin, S., Zanzonico, P. B.,
Koutcher, J. A. & Ackerstaff, E.(2012) Mapping Tumor Hypoxia In Vivo Using
Pattern Recognition of Dynamic Contrast-enhanced MRI Data. Transl Oncol 5,
437-447.
82.
R, S., E, A., H, C., J.A, K. & A, P. in 18th Scientific Meeting & Exhibition of the
International Society for Magnetic Resonance in Medicine.
83.
Shao, Y., Cherry, S. R., Farahani, K., Meadors, K., Siegel, S., Silverman, R. W. &
Marsden, P. K.(1997) Simultaneous PET and MR imaging. Phys Med Biol 42,
1965-1970.
35
84.
Pichler, B. J., Kolb, A., Nagele, T. & Schlemmer, H. P.(2010) PET/MRI: paving
the way for the next generation of clinical multimodality imaging applications. J
Nucl Med 51, 333-336.
85.
Cole, P.(2011) FDA Okays PET/MRI Scanner.
86.
Gambhir, S. S.(2002) Molecular imaging of cancer with positron emission
tomography. Nat Rev Cancer 2, 683-693.
87.
Warburg, O.(1956) On respiratory impairment in cancer cells. Science 124, 269270.
88.
Warburg, O.(1956) On the origin of cancer cells. Science 123, 309-314.
89.
Warburg, O., Wind, F. & Negelein, E.(1927) The Metabolism of Tumors in the
Body. J Gen Physiol 8, 519-530.
90.
Wetter, A., Lipponer, C., Nensa, F., Beiderwellen, K., Olbricht, T., Rubben, H.,
Bockisch, A., Schlosser, T., Heusner, T. A. & Lauenstein, T. C.(2013)
Simultaneous 18F Choline Positron Emission Tomography/Magnetic Resonance
Imaging of the Prostate: Initial Results. Invest Radiol
91.
ViewRay. (2011). ViewRay Demonstrates Potential Therapy Applications for
MRI-Guided
Radiation
at
ASTRO
2011,
Accessed
on
<http://www.viewray.com/press-releases/viewray-demonstrates-potential-therapyapplications-for-mri-guided-radiation-at-astro-2011>.
92.
Stomp, W. (2012). ViewRay Receives FDA Clearance for MRI-Guided Radiation
Therapy
System,
Accessed
on
03/01/2013.
<http://www.medgadget.com/2012/05/viewray-receives-fda-clearance-for-mriguided-radiation-therapy-system.html>.
93.
ViewRay. (2012). Siteman Cancer Center at Barnes-Jewish and Washington
University Begins Imaging with ViewRay System, Accessed on 03/01/2013.
<http://www.viewray.com/press-releases/siteman-cancer-center-at-barnes-jewishand-washington-university-begins-imaging-with-viewray-system>.
94.
Kirby, M., Hirst, C. & Crawford, E. D.(2011) Characterising the castrationresistant prostate cancer population: a systematic review. Int J Clin Pract 65,
1180-1192.
95.
Bubendorf, L., Schopfer, A., Wagner, U., Sauter, G., Moch, H., Willi, N., Gasser,
T. C. & Mihatsch, M. J.(2000) Metastatic patterns of prostate cancer: an autopsy
study of 1,589 patients. Hum Pathol 31, 578-583.
96.
Dahut, W. L., Madan, R. A., Karakunnel, J. J., Adelberg, D., Gulley, J. L.,
Turkbey, I. B., Chau, C. H., Spencer, S. D., Mulquin, M., Wright, J., Parnes, H.
36
L., Steinberg, S. M., Choyke, P. L. & Figg, W. D.(2013) Phase II clinical trial of
cediranib in patients with metastatic castration-resistant prostate cancer. BJU Int
97.
clinicaltrials.gov. (2013). Magnetic Resonance Imaging in Measuring the Effect
of Cabozantinib on Bone Metastases in Patients With Castrate Resistant Prostate
Cancer, Accessed on 03/22/2013. <http://clinicaltrials.gov/show/NCT01599793>.