1. No category

November 2002 vol. 5, no. 2 New Developments in Prostate Cancer Treatment
Androgen
Resistance Part 1
By Charles E. (Snuffy) Myers, M.D.,
Founder and Medical Director,
The American Institute for Diseases of the
Prostate, Charlottesville, VA, and Member
of the PCRI Medical Advisory Board
Editor’s Note: This is the first of a multi-part
article Dr. Myers has written for Insights on
the important subject of hormone resistance.
Subsequent parts that will be published in
future issues of Insights include such subjects as treatment options, the best combination of these options, how to sequence combinations for best effect, maintaining quality
of life while on chemotherapy, the importance of rest intervals from chemotherapy
and future prospects.
Introduction
The development of hormone resistance is the
event most patients with prostate cancer (PC)
fear most. They fear the side effects of
chemotherapy and worry that their survival may
be short. I have seen this fear cause men to simply give up and ask only to be kept comfortable.
This is unfortunate because the best of modern
chemotherapy can be highly effective and the
side effects are usually quite manageable.
What I find particularly tragic is that a
majority of men who are diagnosed with hormone-refractory PC are still hormonally
responsive. All too often I have seen men who
have progressed on Lupron or Zoladex alone be
diagnosed as hormone-refractory and then be
placed on one of the older, toxic chemotherapy
protocols, have a short response of less than a
year’s duration and then be placed on hospice
care. This grim state of affairs is quite unnecessary. The purpose of this article is to describe
what I think is a much more effective
approach.
Is Androgen Withdrawal
Complete?
The basis of hormonal therapy in treating PC is
the reduction of testosterone (T) levels to a
(continued on page 2)
Patient and Physician in Co-Partnership
PCRI/PIA Western Regional
Conference
...a Huge Success!
(see page 8)
Color Doppler and Tissue Harmonic
Ultrasound in the Early Detection
and Staging of Prostate Cancer
Duke K. Bahn, M.D., Chairman and Medical Director, Department of Radiology and
Prostate Institute of America, Community Memorial Hospital, Ventura, CA, and Member
of the PCRI Medical Advisory Board
Transrectal ultrasound (TRUS) imaging has
long been an essential tool for prostate cancer
(PC) diagnosis. In fact, the combination of
prostate specific antigen (PSA) testing with
TRUS and digital rectal examination (DRE)
has been responsible for diagnosing most
prostate cancers in the U.S. each year. Actually,
early detection and early intervention of progressive PC may help to reduce the 30,000
prostate cancer-related deaths each year.
Over the years, increases in the reported
incidence of PC has been disproportionate to
the changes in population demographics. The
main reason for this rapid rise may be the easy
access to PSA and subsequent ultrasound guided biopsies (random biopsy). Ironically
though, this presents a dilemma for the
patients and the clinicians. Although saving
the lives of many men, some men may have
so-called “latent” or “insignificant” tumors
that may not need any treatment.
Precise ultrasound evaluation with proper
biopsy will provide us with valuable information to make a decision between watchful waiting and appropriate early intervention.
Gland Volume and Diagnosis
There is much debate about how to use the
diagnostic tools that we have – DRE, diagnostic PSA levels, PSA in relation to age, and gland
volume – for early detection of PC. In our practice, a serum PSA > 3ng/ml, a PSA increase of
1ng/ml in a year, or abnormal DRE are the
indications for TRUS. If a man’s serum PSA is
greater than the predicted PSA (gland volume
x 0.12), he is in a “high-risk” group for cancer.
(continued on page 6)
Androgen Resistance continued from page 1
Figure 2. Human prostate stained with
Androgen Receptor Ab-1.
Figure 1. Mechanism of Action of Androgens.
range typically found after surgical castration.
The mechanism of action of androgens is
shown in Figure 1. While there is some controversy about the specific T level that must be
attained, most specialists would accept that the
T level must be below 50 ng/dl. I think a more
appropriate goal would be a T level below 20.
When a physician is faced with a patient who is
progressing on hormonal therapy, his or her
first step should be to make sure that the
patient’s T level is in the castrate range. Unfortunately, many physicians assume that administration of Lupron or Zoladex automatically
means that castrate androgen levels have been
attained. This is often not the case. If T levels
are still elevated, the next step is to determine
whether this is the result of inadequate suppression of LH by the LHRH agonist/antagonist
or because of increased production of androgen
precursors by the adrenal gland. In the October
2001 issue of Insights, Dr. Stephen B. Strum’s
article, “Listening to the Biology of Prostate
Cancer,” provided detailed information on how
to determine why medical castration has failed
and how to deal with it.
Androgen Receptor Mutations
An androgen receptor (shown in Figure 2) is
very specific; while it binds avidly to testosterone or dihydrotestosterone (DHT), it does
not react with a wide range of other steroid hormones. For example, the female sex hormones
estradiol and progesterone are chemically similar to T, but the androgen receptor does not
react with either of them. The specificity of this
receptor is critical for normal biology and
allows the prostate and other tissues to respond
selectively to T. The specificity of these receptors
for their various hormones is based on the
structure of these proteins. The androgen
receptor has a portion that fits like a lock and
key with the T molecule.
A minor change in the structure of the
androgen receptor can have profound effects
on its function. For example, there is a strain of
chickens called the Sebright bantam. The
cocks of this strain look like hens. While they
have normal T levels, their androgen receptors
do not function, causing their feminine
appearance. In humans, a similar genetic
change causes what is called testicular feminization syndrome in which males assume the
external appearance of females, including the
development of breasts and female external
genitalia.
The first indication that androgen receptor
mutations might be important in PC came
from an experiment conducted by Dr. George
Wilding at the University of Wisconsin. Wilding
was testing the antiandrogen Eulexin (flutamide) against a human PC cell, LNCaP. In
the test tube, LNCaP responds to T or DHT by
increasing its growth rate. Wilding anticipated
that Eulexin would block the growth stimulation caused by T or DHT. Instead, Eulexin and
its active metabolite, hydroxyflutamide, actually stimulated the growth of LNCaP as if it
2
were testosterone.
Wilding then went on to show that progesterone and estradiol also stimulated LNCaP
growth. The explanation for this unusual
behavior was that the androgen receptor in
LNCaP was mutated in such a way that it reacted promiscuously with androgen, estradiol,
progesterone, and drugs like Eulexin. LNCaP
reacted to all of these compounds as if they
were androgens, because of this altered receptor. These observations led to the prediction
that Eulexin would stimulate the growth of the
cancer in a patient whose tumor possessed an
altered androgen receptor like LNCaP. If the
Eulexin was stopped, the tumor might. shrink.
We now know that approximately 25% of men
who have been on Eulexin for several years and
then develop apparent hormone-resistant PC
will have a significant response when the
Eulexin is stopped.
Even while on hormonal therapy, men continue to produce the female sex hormones,
estradiol and progesterone. Indeed, this is the
reason men on hormonal therapy often experience breast tenderness and enlargement. The
mutated androgen receptor in LNCaP that is
activated by Eulexin also responds to estradiol
and progesterone. Withdrawal of Eulexin does
not remove estradiol or progesterone, and it
seemed possible that its presence may have limited the number of patients who responded to
Eulexin withdrawal. At low doses, the drug Cytadren works by blocking aromatase, the enzyme
that converts T to estradiol. At high doses, it
For any medical terms not familiar to
the reader, please see the glossary at
the PCRI website at:
http://pcri.org/resource/glossary.html
blocks the production of most steroid hormones, including progesterone and all androgens. This led us to substitute Cytadren in men
who were discontinuing Eulexin. Close to 45%
of the patients responded to this treatment.
With Cytadren, it was not possible to determine whether these responses were the result of
the ability of this drug to block estradiol synthesis because it inhibited aromatase or the
result of its ability at high dose to block nearly
all steroid hormone synthesis. Recently, very
specific aromatase inhibitors have been developed, and we tested one of these, Arimidex, in
hormone-refractory PC. We saw no responses,
and I have concluded that the effectiveness
of Cytadren is the result of its capacity to
block nearly all steroid hormone synthesis at high doses.
Casodex is the other widely used antiandrogen. While it is more expensive than Eulexin, it offers the convenience of once-a-day
administration with a lower risk of liver damage and diarrhea. It also appears that the incidence of androgen withdrawal response is
much lower than with Eulexin. In fact,
Casodex can successfully block the growth of
PC cells bearing the mutant androgen receptor
found in LNCaP.
References
G. Wilding, et al. “Aberrant response in vitro of hormone responsive prostate cancer cells to antiandrogens” Prostate 14: 103, 1989
W. K. Kelly and H.I. Scher. “Prostate specific antigen decline after
antiandrogen withdrawal: the flutamide withdrawal syndrome”
Journal Urology 149:607, 1993.
M.A. Fenton, et al. “Functional characterization of mutant androgen receptors from androgen-independent prostate cancer” Clinical Cancer Research 3: 1383, 1997.
S. McDonald, et al. “Ligand responsiveness in human prostate
cancer: structural analysis of mutant androgen receptors from
LNCaP and CWR22 tumors” Cancer Research 60: 2317, 2000.
O. Sartor, et al. “Surprising activity of flutamide withdrawal, when
combined with aminoglutethimide, in treatment of “hormonerefractory” prostate cancer” Journal of the National Cancer Institute 86: 222, 1994.
R.K. Tyagi, et al. “Dynamics of intracellular movement and nucleocytoplasmic recycling of the ligand-activated androgen receptor
in living cells” Molecular Endocrinology 14: 1162, 2000.
Androgen Hypersensitization
In the laboratory, the most widely studied
androgen-responsive human PC cell line is
LNCaP. The growth of this cell line slows or
stops when T is removed. Over a period of
about six months, cells emerge that do grow
slowly without any T. Despite adaptation to the
absence of T for up to six months, these cells
will invariably grow better when T is added and
they still have androgen receptors. However, it
now takes between hundreds to thousands of
times less T to stimulate these cells to grow to
their maximal potential. Instead of becoming hormone-resistant, these cells have
become extraordinarily responsive to
testosterone!
These results have profound implications
for PC treatment. Surgical castration or treatment with drugs like Lupron or Zoladex typically causes a 90–95% drop in blood T levels.
Interestingly, surgical castration causes only a
75% drop in the T content of human prostate
tissue. Even complete androgen blockade,
including medical or surgical castration plus
an antiandrogen such as Eulexin or Casodex,
does not cause a decrease in androgen in the
blood or prostate much beyond 99%. The
implication is that given sufficient time, hormone-responsive PC cells can adapt to grow in
the small amounts of androgen remaining –
even after what has been called complete
androgen blockade has been achieved. In fact,
a large number of drug combinations have
been tested for their ability to reduce T and
DHT levels in prostate tissue. None come close
to reaching levels that would be effective
against cancer cells able to grow in up to
10,000 times less androgen. Yet, we now know
that human PC cells are able to adapt to such
low androgen concentrations.
Increased Androgen Receptor
Expression
There are several paths that PC cells can follow
to become more sensitive to low T levels. These
include increasing the number of androgen
receptors and using one of several means to
enhance androgen receptor efficiency. It is easy
to understand the importance of increasing the
number of androgen receptors. PC cell growth
is controlled by the number of T- or DHTandrogen receptor complexes that are present.
The higher the concentration of androgen
receptors, the more likely it is that enough
receptor complexes will form to fuel cancer cell
growth.
Examination of the androgen receptors
content of human PC specimens shows that
increased expression of androgen receptors is
quite common in patients who have failed
medical or surgical castration. In one study, the
androgen receptor content of 33 untreated PC
cases was compared with 13 cases in which
hormonal therapy had failed. All of the hormone-resistant tumor specimens contained
androgen receptors, and the average amount
was six times higher than in the untreated
patients.
In another study, androgen receptor expression was measured in each patient who failed
castration; the patients were then placed on
complete androgen blockade. Of the ten
patients with increased androgen receptor levels in their cancers, nine responded or experienced disease stabilization because of this
increase in the androgen withdrawal intensity.
In contrast, those patients who had no increase
in androgen receptor content of their tumors
were quite unlikely to respond.
While these results are quite provocative,
the study involved only a small number of men
with cancers that exhibited an increased number of androgen receptors. Much larger numbers of patients need to be studied to determine
the effectiveness of complete androgen blockade in that group of men whose tumors have
developed increased androgen receptor levels.
Nevertheless, it is clear that increased androgen
receptor content is common in patients on hormonal therapy, and that complete androgen
blockade will provide improved tumor
control for many of these patients.
References:
J. Geller, “Basis for hormonal management of advanced prostate
cancer,” Cancer 71: 1039, 1993.
J.D. McConnell, et al. “Finasteride, an inhibitor of 5-alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign
prostatic hyperplasia,” Journal Clinical Endocrinology Metabolism
74: 505, 1992.
G. Forti, et al. “Three-month treatment with a long-acting
gonadotropin-releasing hormone agonist of patients with benign
prostatic hyperplasia: effects on tissue androgen concentration, 5alpha-reductase activity and androgen receptor content,” Journal
Clinical Endocrinology and Metabolism 68: 461, 1989.
P.S. Rennie, et al. “Relative effectiveness of alternative androgen
withdrawal therapies in initiating regression of rat prostate,” Journal of Urology 139: 1337, 1988.
M. Linja, et al. “Amplification and over expression of androgen
receptor gene in hormone-refractory prostate cancer” Cancer
Research 61: 3550, 2001.
(continued on page 4)
3
Androgen Resistance continued from page 3
ability of the androgen receptor to respond to
low levels of T. This process of androgen
receptor phosphorylation appears to play a
major role in allowing PC cells to elude
hormonal therapy.
Figure 3. Dual-color FISH analysis of prostate cancer xenografts. The clustering of red signals
indicates amplification of the AR gene.
C. Palmberg, et al “Androgen receptor gene amplification in a
recurrent prostate cancer after monotherapy with the nonsteroidal
potent antiandrogen Casodex (bicalutamide) with a subsequent
favorable response to maximal androgen blockade” European
Urology 31: 216, 1997.
Increased Androgen Receptor
Efficiency
Androgen receptor complexes form and break
down rapidly. (See Figure 3.) The number of
androgen-receptor complexes present at any
point in time represents a balance between the
rate of complex formation and the rate at
which these complexes break down. A few
papers have described human PC cells able to
grow at low levels of T where the mechanism
seems to involve the formation of much more
stable androgen receptors. For example, Gregory, et al examined human PC cell lines adapted to grow at low T levels. They found that
the combination of increased androgen
receptor content, increased receptor
stability and enhanced nuclear translocation resulted in a 10,000-fold decrease in
the dihydrotestosterone concentration
required for cancer growth! The information is too incomplete for me to tell whether
this occurs with any frequency in patients, but
it illustrates the capacity of PC cells to adapt to
extremely low androgen levels rather well.
There are other proteins in PC cells that
bind to the androgen receptor. Some of these
act to enhance and others to suppress the effectiveness of the androgen receptor. This has
become one of the “hot” areas of PC research,
and it appears likely that shifts in the spectrum
of androgen receptor helpers and suppressors
play a role in allowing these cancer cells to
grow at low T levels. For example, Gregory, et al
reported that a majority of hormone resistant
prostate cancers not only show elevated levels of
androgen receptors, but also show increased
levels of proteins, called coactivators, that make
androgen receptors more efficient. Three activators have been identified that appear to play
a role in hormone-resistance: (1) transcriptional intermediary factor 2, (2) steroid receptor coactivator 1, and (3) ARA70.
References:
C.W. Gregory, et al. “Androgen receptor stabilization in recurrent
prostate cancer is associated with hypersensitivity to low androgen”
Cancer Research 61: 2892, 2001.
C.W. Gregory, et al. “A mechanism for androgen receptor-mediated
prostate cancer recurrence after androgen deprivation therapy”
Cancer Research 61: 4315, 2001.
A. Bubulya, et al. “c-Jun targets amino terminus of androgen
receptor in regulating androgen-responsive transcription”
Endocrine 13: 55, 2000.
Activation of the Receptor at
Low Androgen Levels
After the androgen receptor is made, phosphate
must be added to the protein at certain sites
before it can form effective complexes with T or
DHT.
This process of adding a phosphate to a protein is called phosphorylation. After the androgen receptor binds to T, additional phosphate
groups are added to the protein to facilitate
prostate cell growth. Changes in the cancer cell
that significantly foster the addition of these
phosphate groups can markedly enhance the
4
The epidermal growth factor (EGF) is part
of a family of cytokines that share a capacity to
control the growth of cells. This family of
cytokines plays a major role in the biology of
prostate cells. When the T- or DHT-androgen
receptor complex triggers the growth of human
prostate cells, it does so, in part, because it
causes the prostate cells to release the EGFfamily cytokines. These EGF-family cytokines
then bind to the surface of the prostate cells and
trigger growth. In at least some hormoneresistant cancer cells, EGF-family cytokine
release can occur in the absence of T or DHT,
thus supporting androgen-independent growth.
There are a series of receptors specific for
EGF-family cytokines. One of these, HER-2, is
expressed in both androgen-sensitive and
androgen resistant PC cells. An antibody that
blocks HER-2 is able to prevent the growth of
hormone-sensitive and hormone-resistant PC
cells in mice. One antibody against HER-2,
Herceptin, is already on the market as a treatment for breast cancer.
EGF-family members also appear to play
important roles in the growth of breast, lung,
head, neck, and other cancers. Consequently,
these cytokines and their receptors have
become popular targets for pharmaceutical
companies. Several agents that block this
cytokine family are in late-stage clinical testing
for head and neck cancer and lung cancer. One
of these, Iressa, has received the support of the
FDA advisory committee for cancer drugs and is
likely to become available for the treatment of
lung cancer within the next year. However, once
it is on the market, physicians will be able to
use it for a wide range of other cancers, including PC. I should mention that this drug is
already available in Japan. This drug has two
desirable features. First, it can be given orally,
once a day. Second, its side effects are generally mild and usually limited to an acne-like skin
rash and diarrhea.
IL-6 is another cytokine that appears to
play a role in androgen receptor function. (See
Figure 4.) IL-6 is a cytokine that is released
during infections and other inflammatory diseases. This cytokine is also released by PC cells,
especially in the more aggressive, life-threatening forms of this disease. In PC patients, elevated IL-6 blood levels occur in association with
widespread metastatic cancer and the development of hormone-resistant disease. PC cells
have IL-6 receptors, and the adding of IL-6
increases the phosphorylation of the androgen
receptor. Simply adding IL-6 also stimulates
the growth of hormone-resistant PC cells in
response to T or DHT.
There are no specific medical treatments
that can to block the production of IL-6 by PC
cells or to block the action of this cytokine on
PC cells. However, the body generally produces
IL-6 in response to inflammation at any site.
For example, arteriosclerosis or hardening of
the arteries caused by cholesterol commonly
causes widespread inflammation in the arteries, causing IL-6 elevation. If you are worried
about this, the cardiac C-reactive protein represents the most sensitive and specific test for
widespread inflammation in the body. If it is
positive, you should ask your physician to
determine why your C-reactive protein is elevated and treat this. For example, if it is caused
by hardening of your arteries, the combination
of one baby aspirin and a statin drug, like
Lipitor, can be highly effective.
Neuroendocrine Cells and
Hormone-Resistance
There are a group of specialized cells, called
neuroendocrine cells, which release a wide
range of cytokines and hormones, including
epinephrine, serotonin, calcitonin, gastrinreleasing peptide, and parathormone-related
peptide. These cells are normally found in such
normal tissues as the lining of the lung airways, the gut, breast ducts, and prostate gland
ducts. The products of these neuroendocrine
cells promote fluid secretion and muscle contraction by the ducts in these organs.
Neuroendocrine cells are commonly found
scattered throughout PC masses. In newly diagnosed patients, the greater the number of these
neuroendocrine cells, the more likely a patient
Figure 4. Androgen receptor sensitization by EGF and IL6.
is to develop life-threatening PC. In men on
hormonal therapy, the appearance of large
numbers of neuroendocrine cells in the PC
deposits commonly precede the development of hormone-resistant PC.
For several years, we have known that the
cytokines and hormones produced by neuroendocrine cells stimulate the growth of PC cells in
the test tube. More recently, several of these
neuroendocrine cell products have been shown
to activate the androgen receptor through
phosphorylation, leading to a receptor able to
act at low levels of T or DHT. While there is no
generally accepted treatment designed to suppress these neuroendocrine cells, Sandostatin
has been used with some clinical benefit in a
small series of patients.
In some men, the neuroendocrine cells
become the dominant cell in the cancer and
become very aggressive. These cancers are very
similar to small cell cancer of the lung and
produce little or no PSA. This clinical presentation has recently been characterized by Chris
Logothetis and his colleagues at M.D. Anderson. These patients typically present with rapidly progressing cancer in the presence of a relatively low or normal serum PSA. While there is
no treatment associated with a high response
rate, individual patients have responded well to
combinations of Paclitaxel (Taxol) or Docetaxel (Taxotere) with Carboplatin.
It is possible to monitor the appearance of
neuroendocrine cells in men with PC because
these cells release markers into the blood
stream. The most generally useful test is the
serum chromogranin A (CgA), but neuron spe5
cific enolase (NSE), calcitonin and bombesin
can be of value in individual patients.
Part 2 of this article will appear in an
upcoming issue of Insights.
References:
A. Hobisch, et al. “Interleukin-6 regulates prostate-specific protein
expression in prostate carcinoma cells by activation of the androgen receptor” Cancer Research 4640, 1998.
M.D. Sadar “Androgen-independent induction of prostate-specific
antigen gene expression via cross-talk between the androgen receptor and protein kinase A signal transduction pathways” Journal
Biologic Chemistry 274: 7777, 1999.
L.G. Wang, et al. “Phosphorylation/dephosphorylation of androgen receptor as a determinant of androgen agonistic or antagonistic activity” Biochemistry Biophysics Research Communications
259: 21, 1999.
Z. Culig, et al. “Synergistic activation of androgen receptor by
androgen and luteinizing hormone-releasing hormone in prostatic carcinoma cells” Prostate 32: 106, 1997.
T. Ikonen,et al. “Stimulation of androgen-regulated transactivator
by modulators of protein phosphorylation” Endocrinology 135:
1359, 1994.
C. Culig, et al. “Androgen receptor activation in prostatic tumor cell
lines by insulin- like growth factor 1, keratinocyte growth factor
and epidermal growth factor” Cancer Research 54: 5474, 1994.
D.B. Agus, et al. “Response of prostate cancer to anti-Her-2/neu
antibody in androgen-dependent and –independent human
prostate xenograft models” Cancer Research 19: 4761, 2000.
S. Signoreti, et al. “Her-2 neu expression and progression toward
androgen independence in human prostate cancer” Journal
National Cancer Institute 92: 1918, 2000.
N. Craft, et al. “A mechanism for hormone-independent prostate
cancer through modulation of androgen receptor signaling by the
HER-2/neu tyrosine kinase” Nature Medicine 5: 280, 1999.
Y. Wen, et al. “Her-2/neu promotes androgen-independent survival
and growth of prostate cancer cells through the Akt pathway” Cancer Research 60: 6841, 2000.
S. Yeh, et al. “From Her2/Neu signal cascade to androgen receptor
and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells” Proceedings
National Academy Sciences USA 96: 5458, 1999.
J. Jongsma, et al. “Androgen-independent growth is induced by
neuropeptides in human prostate cancer cell lines” Prostate 42:34,
2000.
Color Doppler and Tissue Harmonic Ultrasound in Early Detection and Staging of the PC continued from page 1
then sample the accompanying neurovascular
• Determine the gland volume with TRUS measurements:
branches tangentially
Gland Volume = [width (w) x height (h) x length (l) x
along a plane just exter0.5]
nal to the prostatic cap• Predicted PSA = gland volume x 0.12
sule. A finding of a tumor
• Excess PSA = serum PSA – predicted PSA
intermixed with fat
• Expected tumor volume = excess PSA/2 (1 cm3 of cancer
produces near 2 ng/ml of PSA)
definitively diagnoses his• To determine average tumor dimension (w + h + l)/3,
tologic stage T3 cancer.
use the 3√ of expected tumor volume.
When outer gland
• Then search for a hypoechoic lesion of this size.
tumors extend to the midline,
we
perform
a
biopsy
of the confluence of
This group is subjected to careful ultrasound
the
seminal
vesicle
and
trapezoid
space of the
evaluation.
apex. The base and apex of the gland in this
Sonographic Evaluation
area are always biopsied to aid in the evaluaBecause clinically relevant (>0.5 cm3) PC is
tion of the internal spread of cancer.
nearly always hypoechoic (black on ultraHypoechoic lesions of the outer gland
sound) compared with normal prostate tissue,
should be pursued vigorously because they can
we only biopsy lesions that are visible by ultraescape when they are relatively small. For this
sound.
reason, we generally perform a biopsy of the
Depending on tumor architecture, the
lesions we see on the ultrasound when excess
degree of hypoechogenicity (darkness on ultraPSA suggests that a 1cm3 lesion may be present
sound) ranges from obvious (nodular) to sub(excess PSA greater 2 ng/ml).
tle (infiltrative) changes. Thus, it is incumbent
If we do not find lesions in the outer gland
on the physician performing the examination
by ultrasound, we generally do not perform
to be familiar with the zonal anatomy and
random biopsies. At this point, we shift our
morphologic presentation of prostate cancer.
attention to the inner gland (transition zone).
Cancers in the outer gland (peripheral
Inner Gland Cancers
zone and central zone) and inner gland (tranTRUS can detect cancers in the inner gland,
sition zone) have different sonographic
though its sensitivity is less than that for the
appearances and biologic behavior, and our
outer gland. If the excess PSA is 4 to 6 ng/ml
threshold that defines whether to biopsy varies
and no lesion is found in the outer gland, one
depending on lesion size, location, and
must carefully scan the inner gland for a
amount of excess PSA.
homogeneous, poorly defined hypoechoic
lesion. We focus on the sites of anatomic weakOuter Gland Cancers
ness of the inner gland, the anterior apex and
Outer gland cancers have a greater propensity
the bladder neck. Color-flow Doppler and
than inner gland cancers for extracapsular
(lately) Tissue Harmonic aid in the diagnosis
spread because they can escape easily through
of these more difficult-to-see inner gland canthe area of anatomic weakness (entry of neucers because most tumors larger than 1 cm3
rovascular bundle branches, seminal vesicles,
have neovascularity (abundant vessel inside of
and apex). Fortunately, these tumors are easy to
tumor) that is easily identifiable with these new
visualize because the background tissue is more
technologies. Given the confusing heterogehomogeneous than that of the inner gland.
neous nature of the transition zone, color-flow
Most outer gland cancers originate lateralmay be the only clue for the presence of cancer
ly at the entrance of the neurovascular bunin a subtle hypoechoic lesion.
dles. To visualize and sample this area, we have
For the inner gland, we take a watchful
found it best to perform the scanning and biopwaiting approach when (1) gland volume is
sy in the transverse plane. When targeting outgreater than 50 cm3, (2) no suspicious lesion of
er gland lesions, we first biopsy the lesion and
Making the Decision to Biopsy
6
the anterior apex or bladder neck area is seen,
(3) excess PSA is less than 4 to 6 ng/ml, and
(4) there is no outer gland lesion. In general,
inner gland cancers have less aggressive prognostic factors (Gleason score and DNA ploidy)
than outer gland cancers and tend to be confined until they attain very large volumes.
Therefore, we feel that these cancers do not
need to be pursued as aggressively as outer
gland cancers. To ensure that we have not overlooked a significant tumor, we repeat serum
PSA testing at 4- to 6-month intervals. Should
an upward trend continue, we re-ultrasound.
Staging Biopsy Technique
The biopsy samples should include one sample
from the middle of the lesion, and all routes of
possible tumor escape based on known sites of
anatomic weakness. The positive neurovascular bundle biopsy has to include fat cells in
contact with tumor cells or the invaded nerve
sheath; a seminal vesicle biopsy should include
pigmented epithelium (specific cell layer of
seminal vesicle). Because the prostate gland
does not contain fat, the presence of this tissue
in the specimen confirms an extraprostatic
invasion. we stain the rectal end of the tissue
core with blue ink before sending it to the laboratory. This will allow us to determine the
exact location of the tumor – an inked end signifies an outer gland (peripheral zone) tumor
and a non-inked end tumor indicates an inner
USING TRUS in PC
Staging and Diagnosis
• Measure gland volume.
• Determine predicted PSA. This
forms our high-risk group.
• Search for hypoechoic lesion in
the outer gland that has a lateral
location.
• Transverse imaging and biopsy of
these lesions is most precise.
Biopsy of the seminal vesicle and
apex should be done when the
lesion extends to the midline.
• Suspect inner gland transition zone
lesions when the excess PSA is 4 to
6 ng/ml and the outer gland is
normal.
• Color-flow Doppler is especially
important for evaluation of the
inner gland.
Urinary
Bladder
gland tumor (transition zone).
Information (Risk Factors) Needed
from TRUS and Staging Biopsy
• What is the exact location of the tumor?
Is it an inner gland or outer gland tumor?
• What is the tumor size in the core by
millimeters and the dimension of the
lesion on TRUS?
• What is the Gleason grade? (If it is 7,
what percentage is 4?)
• Is there a presence of perineural invasion
(PC invading the nerve sheath within the
prostate)?
• Is the tumor contained in the prostate or
not (T1-2 or T3-4)?
• What is the ploidy of the tumor?
This information will provide the exact
local staging of the cancer and will thereby
help the physician and patient choose appropriate a further staging work-up and decide on
eventual treatment options.
State-of-the-Art Ultrasound
Equipment
It is important to use a high-end up-to-date
ultrasound unit for an early detection and
accurate staging biopsy. Power Color Doppler
ultrasound demonstrates all the blood flow patterns inside the prostate. Usually, cancer tissue
shows a higher blood flow (tumor neo-vascularity) than that of normal tissue. This capability will improve detection and actual tumor
size measurement.
The newly developed Tissue Harmonic
technology improves spatial resolution to permit visualization of smaller objects and
improves contrast resolution to discern very
subtle differences in grayscale. This is different
from conventional ultrasound imaging, which
sends out a burst of sound and listens for that
burst to echo off structures in the body, (an
echo that is usually weak and distorted). The
time it takes for the echo to return is proportional to the distance the sound wave traveled.
In Tissue Harmonic technology, instead of listening for the same sound burst to return in the
echo, the ultrasound equipment listens only for
a sound burst at twice the transmitted frequency. Good ultrasound evaluation with staging
(strategic) biopsy may eliminate an unneces-
Bladder
Neck
Urethra
Seminal
Vesicle
Apex
Base
Cancer
NVB
NVB
Sagital Plane of Prostate: The black area represents cancer. It easily spreads to the adjacent
neurovascular bundle (NVB), to the seminal vesicle, and the bladder neck.
Site of Anatomic Weakness
of the Outer Gland
(Peripheral and Central Zones)
Site of Anatomic Weakness
of the Inner Gland
(Transitional Zone)
• Feeding Branches of
Neurovascular Bundle (NVB)
• Seminal Vesicle Junction with
Central Zone
• Seminal Vesicle confluence
• Trapezoid Space at Apex
• Junction of Prostate Capsule and
Anterior Fibromuscular Stroma
• Bladder Neck
• Apex of Transitional Zone
• Junction of Prostate
Capsule and Anterior
Fibromuscular Stroma
Tumor
Vascularity on
Color Doppler
Subtle
Lesion on
Grey Scale
Axial Planes of TRUS: There is a very subtle lesion in the right mid gland in the transition zone
on the gray scale ultrasound (right side picture). It can be easily overlooked. The Color Doppler
study (left side picture) clearly delineates the lesion with tumor vascularity (neovascularity) and
the actual size of the tumor. This case was proven to be Gleason 7 with an extracapsular extension of the tumor.
(continued on page 10)
7
A Knowledgeable
PC Survivor Rates
the Conference
Editor’s note: We had barely gotten home
from the conference when Harry Pinchot
received an e-mail from Aubrey Pilgrim, a
prostate cancer survivor who had attended
the conference. Aubrey is a very special survivor in that he has written several books on
the subject, the most recent of which is A Revolutionary Approach to Prostate Cancer.
What’s more, Harry Pinchot regards him as “the
most knowledgeable person I know on the subject of impotence.” Hence, Aubrey’s opinion of
the conference was very rewarding for us.
I am sorry for all those who missed the PCRI/
PIA Conference today. They had originally
planned on about 400, but they moved the
conference to the USC Norris Cancer Center
and it looked like about twice that many
showed up (554 to be exact, ed). They provided a breakfast of different fruit, bagels
and non-fat cream cheese, coffee and
juice. They also provided a box lunch. All
this for a cost of $10, or $15 for couples.
We had some excellent speakers:
Dr. Stephen Strum, Dr. Mark Scholz,
Dr. Stephen Tucker, Dr. Samuel Kipper,
Dr. Glenn Tisman, Dr. Fred Lee, Dr. Duke
Bahn, and several others.
The highlight of the Conference was
when Dr. Duke Bahn did biopsies of
three men on stage using the Color
Doppler Ultrasound system. (One feature
of the conference was a free PSA test.) Dr.
Lee stood out in front and did a running
commentary as the camera showed Dr.
Bahn doing the biopsies that were projected onto a large screen.
The Color Doppler Ultrasound system is truly
amazing. He showed the prostate with a normal black and white ultrasound, then the color doppler image alongside it. The red blood
vessels of the tumors showed up like a lighthouse beacon. He then took a biopsy gun and
you could see the needle tracks through the
center of the tumors.
Awhile back there were a lot of messages about
biopsies and pain. But the men did not move a
muscle when they were biopsied. Someone
asked if the men had been sedated or given an
anesthetic. Dr. Lee said that he had done thousands of biopsies, but had only used an anesthetic on two men.
They made videotapes of the conference.
They are offering the tapes for $15 each or all
seven tapes for $99 plus shipping charges.
If any are interested, I can provide more
info.
I wish you all the best.
Aubrey Pilgrim, DC (Ret.)
[email protected]
Western Regional
PCRI
a
Conference
Comments like these were the
order of the day as the Western
Regional came to its conclusion on
Saturday, October 5 at the University of Southern California’s NorrisMayer Teaching Center in Los
Angeles. Jointly staged by the PCRI
and the Prostate Institute of America (PIA), the conference attracted
554 lay people and medical professionals vitally interested in developments and treatments of PC.
The crowd gave rapt attention to the
experts who presented current infor-
“
“I don’t think I have ever learned
so much in one day as I did at
your conference last Saturday”
”
“You were right – the conference
was something not to be missed”
mation on diagnosing and staging prostate
cancer, primary therapies, therapies for systemic and recurrent prostate cancer, and
therapies for advanced prostate cancer.
The speakers included some of the most
distinguished doctors and researchers in
A Tale of
Three Seniors
and
”
PIA
…a Huge Success!
the prostate cancer community. Among
them were (alphabetically) Drs. Duke
Bahn, Marc Botnick, Stan Brosman,
Michael Dugan, Mitchell Gross, Samuel
Kipper, Richard Lam, Fred Lee, Bob Leibowitz, Leonard Marks, David Quinn,
Richard Reisman, Mark Scholz, Stephen
Strum, Glen Tisman, and Steven Tucker.
Volunteers
Made It Happen
In the aftermath of the Western Regional
Conference, we received many compliments
on how smoothly everything went. “Well,”
PCRI Executive Director Glenn Weaver
asserts, “That didn’t happen by accident. It
was the result of a great effort by all the volValuable though they were, these presenunteers who pitched in to help the PCRI staff
tations were not the only features of the
(Harry Pinchot, Gail Betts, Victor Grimaldo, and Jim O’Hara) do all the setup, regisConference. Free PSA tests were given to
ter the attendees, arrange for the PSA test
almost 200 men in the morning, and they
Glenn D. Weaver, Executive Director of the
blood drawing, answer all the questions
had the results by the noon break.
PCRI (left), and Dr. Duke K. Bahn, Medical
attendees came up with, and, at the end of
Director
of
the
PIA.
(continued on page 16)
the day, remove all of the signs and materials so that the USC medical center returned
to its pre-Conference condition.”
So once again, hats off and heartfelt
thanks to the 32 volunteers who did so
much to make the Conference such a
success. Here they are in alphabetical
order: Esther Ames, Barbara Bornt,
Robert Bornt, Heidi Buccino, Eileen
The audience watching the large screen on stage was fascinated by Dr. Duke Bahn’s
Call, Paul Crossman, Jed Derry,
examination of three men, using Color Doppler and tissue harmonic ultrasound followed
Liz Derry, Bob Each, Ken Foster,
by targeted needle biopsies. But for the three men, bigger stakes were involved; they
Diana Garnand, Tom Gibson, Hal
were to find out from this examination whether their high PSAs portended prostate canGoodman, Brad Guess, Tammy Hall,
cer and if so, how serious it was.
Christine Hermosillo, Inge Jones,
Belle Jurman, Aram Kantarian, Mark
Marcus Stone, 70, Gil Haimson, 69, and Ron Dixon, 67, all had somewhat different
Kline, Anthony Lee, John Loesing,
symptoms, but all had worrisome PSA levels. Mr. Stone had been adopting a watchful
Gail Mastright, Mary Nishimura,
waiting strategy for high but fluctuating PSA levels with an episode of prostatitis:
Jill Peck, Carl Pernicone, Lew Pfeffer,
however, he was concerned that his PSA, taken that morning, had risen to 9.9.
Dee Pinchot, Mercedita Ramos, Jackie
Mr. Haimson had been diagnosed as having prostate cancer, but, believing surgery or
Salcedo, Charles Uche and Dana
radiation were his only options, elected instead to adopt a watchful waiting strategy,
Vaughan.
changing his diet and taking a series of vitamins, minerals and nutrients, including
lysine, selenium, and Vitamin C. However, when he had his PSA taken that morning
he discovered it had risen from 5.5 to 7.9 in 2002. Mr. Dixon had been diagnosed
with prostate cancer in 1996 and had it treated then with Photon/Proton beam therapy in 1997. His PSA dropped to as low as 0.9, but then began to slowly rise and
in 2000 was 2.0. By October 2001, it had risen above 3 and had fluctuated up and
down in 2002 but never less than 3.0 and sometimes as high as 3.5.
The biopsy results came in the following week. Marcus Stone was relieved, even
elated, when his diagnosis proved to be Prostatitis. He would require treatment for
this ailment, but at least it wasn’t prostate cancer. Conversely, Gil Haimson learned
that two of the cores biopsied from his left lobe revealed prostate cancer (as had
been seen on the color ultrasound display), and his Gleason score had risen from
6 to 7. However, there was no evidence of a tumor extension outside the
prostate. Regarding watchful waiting as no longer a viable strategy, he is now
embarking on a program to find the best treatment strategy to adopt. Ron
Dixon also got sobering news from the biopsy results. As had been seen on the
color ultrasound display, his cancer had spread to the bladder neck and the seminal vesicles, so his clinical stage had gone to T4 from T2b. Without delaying further, he started ADT3 therapy the very next week.
Three biopsies, three different diagnoses. And each of those men now has a clear
picture of his condition that will be important in selecting the optimum treatment.
Prostate Institute
of America
Dr. Duke K. Bahn, PIA Medical Director, at
his Color Doppler Ultrasound system.
PCRI’s partner in staging the Southern California
Regional Prostate Cancer Conference in Los
Angeles is a new organization, the Prostate Institute of America (PIA). Located at the 240-bed
Community Memorial Hospital (CMH) in Ventura, California, the institute has a unique mission:
“the accurate staging of Prostate Cancer and
providing options that include minimally
invasive therapies, including Brachytherapy
and Cryosurgery, as a means of enhancing
survivability.”
Recognizing that many of you readers might
not be familiar with the PIA, your editor drove up
to Ventura at the invitation of Dr. Richard Reisman, the Medical Director of CMH, to get a look
at the new institute. Dr. Reisman told me he had
first encountered PCRI at a regional conference
several years ago. There he met PCRI”s Harry
Pinchot and in the course of their conversation
mentioned that he was dissatisfied with the state
of the art of blind biopsies. Pinchot told him of
Dr. Duke K. Bahn, a renowned expert in the
prostate cancer community who was focusing on
ultrasound and biopsy diagnosis of PC at Crittenton Hospital in Rochester, MI. (Editor’s Note: An
article Dr. Bahn wrote for Insights describing his
ultrasound techniques appears in this issue, and
his paper on the outcomes of cryosurgical ablation treatments of 590 of his patients just
appeared in the August issue of Urology).
Dr Reisman and Dr. Michael Bakst, CEO of
CMH, visited Crittenton Hospital and both were
most impressed with Dr. Bahn and the Crittenton
Prostate Center he and Dr. Fred Lee had created
there. Seeing the potential of establishing a similar Prostate Cancer Center on the West coast
alongside CMH’s Breast Cancer Center, Dr.
Reisman persuaded Dr. Bahn to relocate to California and create a world-class prostate cancer
treatment center at CMH. Dr. Lee is now at Wayne
State University.
Thus was PIA born, and with Dr. Bahn as
Medical Director, PIA is already making strides
toward that goal. Located on the fourth floor of
the hospital’s medical building, it has an efficient
layout, incorporating such state-of-the-art
prostate care equipment as a Color Doppler Tissue Harmonic Ultrasound machine and cryotherapy surgery equipment, each of which cost a
quarter of a million dollars.
At his meeting with me, Dr. Bahn stressed
PIA’s capability for the early detection and staging
of PC. “We can do the entire detection and staging process right here in less than a day so that
patients don’t have to keep going to different centers on different days to get this basic information,” he said. “Here, we can get PSA results in 15
minutes and, if indicated, take the patient to the
adjacent room and get a precise location of the
cancer using our Color Doppler Tissue Harmonic
Ultrasound system. Then, without delay, we can
biopsy the areas of the prostate pinpointed by the
ultrasound. And we have bone scan and CT scan
equipment available to complete the diagnosis
and staging.”
The Color Doppler machine is indeed impressive as those of you who witnessed the demonstration at the October 5 conference can attest,
and according to Dr. Reisman, PIA intends to
start early PC detection drives featuring free PSA
tests beginning this October. Clearly, PIA has
shown a willingness to invest in the talent and the
facilities needed to be an effective new entrant in
the prostate cancer community in its drive to
eliminate the threat of PC in our lifetime.
Color Doppler and Tissue Harmonic Ultrasound in Early Detection and Staging of the PC continued from page 7
sary endo-rectal MRI study (that is still an
imaging study without tissue confirmation).
Moreover, it will eliminate the “guesstimation”
from random biopsies. Currently, we use the
Hitachi EUB-6500 Ultrasound model.
Soon, there will be further developments in
TRUS that will include contrast (IV form of
micro-bubbles), enhanced Color Doppler, and
three-dimensional imaging capability.
The Role of TRUS-Guided
(Not Random) Biopsies in
Determining the Internal
and External Spread of PC
Dr. Fred Lee and I published our data comparing sextant (random) biopsy proven PC data
with our staging biopsy data on 110 men. All
men came to us for a second opinion with
known cancer. We performed TRUS with repeat
staging biopsies on all of those men. (Seminars
in Urologic Oncology, Vol 16, 1998, p 129-136.)
The results were as follows:
• 26% of the Stage T1-T2 (tumor confined
within the prostate) cancers defined by
sextant biopsy were upstaged to T3-T4
(non-confined) by our staging biopsy
technique.
• The Gleason sum was also higher in our
staging biopsies.
• Perineural invasion was demonstrated
in 52% of staging biopsies compared to
21% in sextant biopsies.
• Diagnosing unsuspected extracapsular
extension and perineural invasion objectifies the choice of definitive treatment.
Conclusion
Current methods for determining confined PC
for the individual patient are only guesstimations. The pathological outcomes for clinically
confined PC have only a 50% probability of
being correct. Today’s patients seek answers
through patient advocacy groups, Internet
surfing, and scientific literature. When one of
10
our patients consults with the “specialists”, he
quickly surmises their uncertainty.
In our hands, the use of state-of-the-art
TRUS with Color Doppler and Tissue Harmonic has helped us and others resolve the uncertainty of whether a cancer is or is not confined
and what other risk factors they may have.
Then, and only then, do we more reliably predict a prognosis and guide our patients to those
treatments that are most appropriate for them.
References
McNeal J: Cancer volume and site of origin of adenocarcinoma in
the prostate: Relationship to local and distant spread. Hum Pathol
23:258-266, 1992
Lee F: Prostate cancer: Transrectal ultrasound and pathology comparison. Cancer 67:1132-1142, 1991
Epstein J. Corellation of prostate cancer nuclear deoxyribonucleic
acid, size, shape and gleason grade with pathological stage at radical prostatectomy. J Urol: 148:87-91, 1992
Bostwick D. Optimized microvessel density analysis improves prediction of cancer stage from prostate needle biopsies. Urology 48:
47-57, 1996
Lee F. Bahn D. The role of TRUS-guided biopsies for determination
of internal and external spread of prostate cancer. Seminars in Uro
Oncology 16: 129-136, 1998
What
Others
are Doing
CaP CURE – Association for the
Cure of Cancer of the Prostate
CaP CURE is a non-profit public charity established with a single mission: to
end prostate cancer as a health risk to all men and their families. To achieve
this goal, CaP CURE takes a unique approach to beating the disease: rapidly,
and with little red tape, fund top scientists and physicians to deploy venture
research programs that will benefit prostate cancer patients in the near term.
In addition, CaP CURE funds a network of clinical investigators at major cancer centers that are developing new treatments for prostate cancer. Since its
founding in 1993, CaP CURE has awarded more than $100 million to over
1000 research projects. CaP CURE-supported scientists and clinicians have
made tremendous progress with more than 80 research projects now in clinical trials.
Clinical trials support the CaP CURE mission of finding a cure for prostate
cancer. One of the biggest obstacles to finding a cure or control for prostate
cancer is a lack of participants for clinical trials. Patients who participate in
clinical trials have access to the most innovative, advanced experimental
treatments for prostate cancer. Clinical trials offer the possibility of a clinical
response while contributing to scientists’ understanding of the disease and
how it can be conquered. We urge patients who may qualify for these studies
to discuss participation with the indicated medical institutions or with their
personal physician.
Clinical trials are conducted in three phases. Phase I determines how the
body reacts to increasing doses of the experimental treatment. Phase II tests
are a preliminary determination of the treatment’s effectiveness at the safe
dose. Phase III tests the experimental treatment against established therapies,
and studies are conducted on a much larger scale than in the two previous
phases.
This page contains descriptions of some of these clinical trials. Many
others can be seen by accessing the CaP CURE website, www.capcure.org. If
you are interested in participating in a clinical trial, simply contact the participating institution directly. If you have questions about CaP CURE, please
contact Dr. Howard Soule, CaP CURE Chief Science Officer at
[email protected].
Within the Prostate Cancer
community are many organizations
and Prostate Cancer centers other
than PCRI that are doing innovative and valuable work in battling this disease. Commencing
with this issue of Insights, we shall endeavor to
familiarize our readers with as many of these sister organizations as possible.
Clinical Trials
By Robert Each, CaP CURE
Clinical trials are a necessary step in moving drug development from
the laboratory to the patient population. Since its inception in 1993,
CaP CURE has awarded tens of millions of dollars to basic research
with the hope it will stimulate development of new drugs and vaccines
to battle this disease. In the last few years, some of this basic research
has begun to reach the clinical environment. Analyzing some of these
trials, I came up with five that I find rather intriguing. I have broken
these five studies down into two groups; the first group consists of projects studying existing drugs or a soon to be approved (we hope) drug,
and the second group involves leading edge therapies.
Massachusetts General Hospital Cancer Center is conducting
a study that could treat or even prevent bone lesions from forming. It
combines a third generation bisphosphonate, Zometa, with an
endothelin-1 receptor antagonist called Atrasentan. Zometa has been
approved for treating prostate cancer bone metastases and works to
reduce bone resorption or break down of the bone material. Atrasentan
seems to inhibit bone building by targeting a protein called endothelin-1, which promotes cell growth in bone and which is overexpressed
(found in unusually high numbers) in prostate cancer cells. The study
will be separated into at least two groups; the first group will receive
Atresentan alone and the second group will receive Atresentan and
Zometa. Should the two drugs work well together, we will have a valuable therapy for slowing or reducing bone involvement with or without
hormonal therapy. Unfortunately Astrasentan is still in phase 3 trials so
the average Prostate Cancer patient will not be able to access it until it
is FDA approved. FDA approval is expected sometime next year.
Another interesting study, using completely available drugs, is
being done at the University of Wisconsin Comprehensive Cancer
Center. The study combines one of two vitamin D analogs, doxercalciferol (Hectorol) or calcitriol (Roccaltrol), with docetaxel (Taxotere).
Both types of drugs seem to inhibit prostate cancer growth, but there
seems to be a synergy that increases the response rate of the docetaxel
when it is combined with these synthetic vitamin D analogs. The
researchers are attempting to gain a better understanding of the interaction between the drugs and determine optimal dosing.
M.D. Anderson is studying a proteasome inhibitor drug, PS-341,
that has shown promise in multiple myloma and non-Hodgkin’s lymphoma. Proteasomes are enzymes that play a role in cell cycle regulation and protein degradation. Proteasome inhibitors can arrest the
growth of tumors and reduce the spread of cancer, and PS-341 is an inhibitor
of the ubiquitin-proteasome pathway and has been shown to inhibit cell growth
signaling pathways and cause apoptosis. Toxicity is being tested presently and
trials should begin when dosages are established.
Cornell University is working on a monoclonal antibody, mab hu591,
which seeks out any cell that shows prostate-specific membrane antigen
(PSMA) on its surface. PSMA is made by normal prostate cells; however it is
made in higher amounts in prostate cancer cells and, in particular, even higher amounts in advanced prostate cancer. A cytotoxic agent is attached to the
antibody and when the antibody finds a cell with PSMA on its surface, it attaches itself and the cytotoxic agent to the cell. The cytotoxic then goes to work, and
the result is a dead cancer cell. The cytotoxic agents being investigated are both
radiometals such as Yttrium and chemicals agent such as Interleukin-2.
Perhaps the most interesting study is another monoclonal antibody being
researched at Cedars-Sinai Prostate Cancer Center. This “mab” goes by the
name 2C4 and seems to inhibit the activity of several types of human epidermal
growth factor receptor proteins. It is a single agent that both hunts and kills the
cancer cell, similar to the way Herceptin works for breast cancer.
If you are interested in any of these trials, please contact the respective institution or check its website for eligibility and availability.
11
More Than Just
A
Primer
Webster defines a primer as “a small introductory book on a
subject.” Well, the Life Extension Foundation’s new publication,
A Primer on Prostate Cancer: The Empowered Patient’s
Guide by Stephen B. Strum, M.D. and Donna Pogliano, is
much more than that. With over 350 pages and full color illustrations, this book contains the latest information on prostate
cancer, its diagnosis, and its treatment in a form that can be
readily assimilated even by those who are just beginning to
learn about the disease.
Among the unique features of this book are eighteen case studies Dr. Strum presents to illustrate such important but difficult
concepts as “the importance of comprehensive tumor marker
analysis in the setting of Gleason Scores of 8 to 10.” Moreover,
each chapter has a succinct summary entitled “What You
Should Have Learned From This Chapter,” and there is a glosDr. Stephen B. Strum and Donna
Pogliano at the Western Regional
sary containing definitions of more than 300 of the technical
Conference on Prostate Cancer.
terms and acronyms used by the prostate cancer medical
community.
The book is unusually well researched, too. It contains over 150 references to published papers and other source documents that readers can
easily access. And a special Appendix describes Prostate Cancer Resources complete with website and/or e-mail addresses to enable readers to
find support groups, books, newsletters, etc. so they can stay current with on-going developments in PC.
As we said, it’s much, much more than a primer and fully justifies its price of $28.95. Moreover, the book is available from PCRI for $21.00 plus
3.95 shipping and handling. Call 310-743-2116 or access the PCRI Website at www.pcri.org. And see our special offer on page 15.
Funding
We find ourselves continually amazed at the
effort and ingenuity people devote to raise
funds for the fight against prostate cancer.
Memorial funds, fund-raising dinners, neighborhood sales, and the like raise serious funds
and provide a lasting tribute to men afflicted
by this disease.
The most recent example of this occurred when a young prostate
cancer widow, although stunned by the premature death of her husband, did not let her grief overwhelm her. Instead, she became determined to organize efforts that will help others steer clear of premature
death due to prostate cancer. And Carol Kover realized that that goal
takes money. Her first step was to have the PCRI set up the Phil
Kover Memorial Fund at its headquarters at 5777 W. Century
Blvd., Suite 885, Los Angeles, CA 90045. Friends, family, and acquaintances of the Kover family could then make direct donations to the
PCRI in Phil Kover’s name in the form of cash or money order.
That was very effective, but Carol Kover was just getting started.
Aided by friends and family, she set about to sponsor an annual golf
tournament at her local Ohio golf course to raise money for the Phil
Kover Memorial Fund. An admission fee of $80 covered costs for the
golf, a cart, door prizes, and a dinner, as well as a contribution to the
fund. She also solicited hole sponsorships of $100 per hole.
In all, 32 four-person teams signed up, and the tournament went
ahead as scheduled on October 4, 2002 despite the fact that it rained.
Only 13 of the 32 teams were able to finish, but nonetheless the tour-
the Fight Against
Prostate
Cancer
nament was a big success. To quote Carol
Kover:
“It looks like we netted $7000 for
PCRI which I think is great for my first
time fundraising at a golf outing. Most
local outings only net about $2500. All
128 golfers showed up. Many golfers
offered larger contributions for next year. We had several
speakers, and I also encouraged local contributions to PCRI
for our ongoing Phil Kover Memorial Fund federal campaign.”
Clearly, Carol Kover is not stopping with this successful effort. She
has bigger and on-going goals in mind – including a tournament next
year. Through these efforts, she is succeeding in keeping Phil Kover’s
name alive and at the same time fighting the disease that killed him.
We know that Carol Kover is one of many people touched by
prostate cancer who wouldn’t let the disease defeat them, who organized their family, friend, business associates, and community to raise
funds to help the PCRI fight PC. If you are involved in such a campaign, we salute you, and we hope you will share your experience with
us and our readers as Carol Kover did.
Editor's Note: Just as we were going to press with this article,
Carol e-mailed us the sad news that she, herself, had been
diagnosed with Stage 4 breast cancer, and she began
chemotherapy on Monday, November 4. Her reaction to the
news? “Now I have my own battle to fight, and Phil
taught me the way. It’s the only way. We're fighters!”
(continued at right)
12
Meet PCRI’s
Medical Advisory Board
To manage the expanding volume of knowledge about prostate
cancer and translate it into useful, understandable recommendations for patients, the PCRI has formed a medical advisory board
of 18 eminent physicians representing seven medical disciplines.
We will introduce these physicians to Insights readers in this and
upcoming issues. This issue features two men, Dr. Charles E.
Myers and Dr. Duke K. Bahn, each of whom has written an article exclusively for Insights readers and appears in this issue.
Charles E. (Snuffy) Myers, M.D. is
one of the most influential men in the
field of prostate cancer research and
treatment. After graduating near the
top of his class at the University of Pennsylvania School of Medicine, he spent
the next 25 years with the National
Cancer Institute in Bethesda MD, rising to the position of
Chief of NCI’s Clinical Pharmacology Branch. In 1994, he
accepted a position as Director of the Cancer Center at the
University of Virginia and soon built it into one of the leading
centers for prostate cancer research. Early this year, he left
UVA to establish the American Institute for Diseases of the
Prostate, which focuses on providing comprehensive management of prostate cancer. Dr. Myers tailors treatment according
to the needs of each patient, based upon both his knowledge
of the disease and his own experience as a PC patient.
Blazing Trails
Project
Peter Briner is a 30-year-old firefighter in the
Seattle area whose mission is to raise the
awareness of the importance of early testing for
prostate cancer in order to save lives. To quote
him directly, “My grandfather died of prostate
cancer and four of his five sons, including my
Dad, Paul Briner, have prostate cancer. Therefore, there is a good chance that I will likely
have it, too. As a result of a PSA test in 1995, my
father was diagnosed with prostate cancer at
the age of 54 and is currently undergoing treatment that we hope will prolong his life. My
grandfather might not have died from it, in
1968, if early detection had been possible. Since
early detection is available now, I want to get
the word out so that everybody will be aware of
the importance of early detection and start testing at an early age. Of course, getting the word
out takes money.
“A couple of years ago, I learned about the
Western States Endurance Run that is held
every June in northern California. It is a 100mile race over a rugged country trail, and it
takes most of the 400 or so runners between 24
Duke K. Bahn, M.D. is internationally
recognized as one of the world’s leading practitioners in the study and treatment of prostate cancer. He is now
Medical Director of the new Prostate
Institute of America, a position he
accepted after more than ten years at
the Crittenton Hospital Medical Center in Michigan.
Dr. Bahn has, with his mentor Dr. Fred Lee, performed more
than 35,000 PSA tests, conducted 13,500 ultrasounds,
done 7100 biopsies, and diagnosed more than 2500 cases
of prostate cancer during the last seven years. In addition,
they have performed more than 900 cryosurgery procedures, compiling the largest follow-up data yet of men who
have undergone this treatment. That data was the impetus
for obtaining Medicare approval for cryosurgery as a viable
treatment for prostate cancer.
and 30 hours to complete the run. I was particularly interested in it because my
grandfather had helped mark this historic
gold rush trail 70 years ago. I thought that
this race would be a fitting way to raise
both funds and awareness for prostate
cancer. That was the genesis of the Blazing
Trails project.”
Largely because of the urging by Peter and
Paul Briner, the 2001 race was dedicated to a
cause for the first time since its inception in
1974. The Western States Endurance Run
Foundation agreed to promote the cause of
prostate cancer awareness and provide the
opportunity for every appropriate male runner
to be given a PSA screening test without charge.
In addition, the Briners arranged for newspaper and television coverage of the Blazing
Trails project and sought sponsors to help support organizations that are actively promoting
the critical need for early prostate cancer detection and treatment. That is when Paul Briner
first contacted the PCRI.
“We wanted to do even more than just raise
money,” Paul Briner recalls. “So we came up
with the idea of passing out a descriptive handout describing the detection and treatment of
13
prostate cancer in layman’s terms. I contacted
Dr. Stephen Strum of the PCRI, and he generously agreed to write the medical text for this
descriptive brochure. With the money coming
in from the Blazing Trails project, we were able
to produce and print 15,000 copies that we distributed to each race entrant, to the press, and
to various sponsor organizations for distribution to their employees.
“All in all, we collected over $11,500 with
only $3000 in expenses, so Project Blazing
Trails was able to raise $7000 for PCRI programs, plus the project was directly responsible
for a brochure that describes the prevention
and detection of prostate cancer in terms that a
lay person can understand.”
Actually, the project did even better. The
PCRI enhanced the brochure design, and the
Life Extension Foundation proceeded to print
50,000 complimentary copies that the PCRI
has distributed nationwide in an outreach program to men at risk from prostate cancer.
Thus, a nationwide awareness program has
resulted from Peter Briner’s mission and his
determination to fulfill that mission. And
speaking of determination, Peter completed the
race in 27 hours and 29 minutes.
Empowerment
Through Knowledge
ST IT UT E
ER RE SE AR CH IN
NC
CA
TE
TA
OS
PR
geles, CA 90045
vard, Suite 885, Los An
5777 W. Century Boule
rostate-cancer.org
w.p
ww
•
(310) 743-2113
(310) 743-2116 • Fax
ny of whom were facing imporDear Subscriber,
with men and their families, ma
talk
we
to
nity
ortu
opp
the
had
nce, we
son for the PCRI and the help
At the recent Regional Confere
in we were reminded of the rea
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ase
And
dise
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nin
can
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frig
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tant decisions thrust upon them
of knowledge that can empow
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the
in
possible
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the
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can provid
more about prostate cancer and , the
and
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after all, the medical commu
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Why is this needed? Each day,
more researchers learn and the
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tment options for men diagase
treatment options to end this dise cancer patients can grasp. Today, the number of different trea e cancer is producing an
state
prostat
less useful knowledge most pro and intimidating. And new research about the treatment of
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larg
is
nosed with prostate cancer
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offer knowledgeexplosion of new useful inform
through all this information and
sift
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are diagnosed each
cancer patients rely
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s. However, des
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year, there are fewer than 50 onc
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That’s why the PCRI was establis
of a Medical Review Board con
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patients and physicians have
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of prostate cancer.
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nity in five different ways:
edgeable experts in the prostat
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iew Board for medical advice.
to medical
expertise of PCRI’s Medical Rev
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info
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ts so far this year.
2. PCRI’s Website (www.pcri
bsite has had over 400,000 visi
We
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articles, news, and even soft
information about prostate can
to disseminate state-of-the-art
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and
embarked on an exp
e Institute of America, hosted a
4. Conferences. The PCRI has
in partnership with the Prostat
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PCR
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Thi
re.
ratu
most of whom were prostate can Conference will
s,
demonstrations, and lite
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re. In 2003, the East Coast
conference in Los Angeles tha
t coasts are planned for the futu
wes
and
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eas
the
on
ting
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alte
nual conferences
ortant research papers
be held in Washington, D.C.
PCRI this year published two imp
,
ogy
col
On
ch
Tou
ling
Hea
h
junction wit
Prostate and the Journal of
5. Publications. Working in con cer response and the effectiveness of food supplements in The
Prostate Cancer Primer.
can
lication of a landmark 300-page
on the topics of parameters of
pub
the
red
nso
spo
coI
PCR
the
ition,
their families who have
Cancer and Nutrition. In add
donations from individuals and
us
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gen
from
tes
ina
orig
g
oing efforts of PCRI and
PCRI fundin
erous donation to fund the ong cer.
gen
a
The overwhelming majority of
g
kin
ma
in
m
the
join
l
can
e you wil
ough their battle with prostate
endured prostate cancer. We hop
wledge that will help them thr
kno
the
n
gai
ts
ien
pat
cer
can
help prostate
Mark Scholz
Co-Founder
Chester A. Swenson
President
14
How to
Contribute
to the
PCRI
You can support the Prostate Cancer Research Institute
(PCRI) in several ways:
• A direct donation of cash (check or credit card), stock or real estate
• Memorial and “Gift in Honor” Contributions: Honoring someone you
care about with a memorial or commemorative gift
• Planned Giving: Naming the PCRI in your will or as beneficiary of a life
insurance policy.
Direct Donation
Your tax-deductible gift in the form of cash, stocks or real estate should be
made payable to the Prostate Cancer Research Institute and sent to:
Prostate Cancer Research Institute
5777 W. Century Blvd., Suite 885
Los Angeles, CA 90045
Federal Tax ID Number: 95-4617875
Credit card donations can be made online at www.pcri.org.
Donation of Property
The PCRI accepts property donations from interested donors throughout the
U.S. Those who wish to donate cars (in Southern California only), boats,
jewelry, art, real estate or other property should call toll-free:
1-800-203-2940. Your donation is tax-deductible, and there is free towing for
donated cars anywhere in Southern California. A free appraisal service is
available.
“Gift in Honor” and
Memorial Contributions
A gift to the Prostate Cancer Research Institute can be a special way to give
tribute. These gifts are a gratifying way for individuals, organizations, businesses and groups to honor someone while supporting the Prostate Cancer
Research Institute’s mission to prevent and cure prostate cancer and to
improve the lives of all men affected by the disease.
With each “gift in honor” contribution received, a letter is sent to the appropriate person named – please include the name and address of the person you
would like to be notified of your contribution. The amount given is never indicated in the letter. The donor, however, will receive an acknowledgment letter. A “gift in honor” is a special way to recognize a friend or loved one’s birthday, anniversary or other important event while also benefiting the
Foundation.
A memorial contribution is a particularly meaningful way to remember
deceased friends and loved ones while helping the Institute expand its important programs.
You can send your memorial or “gift in honor” of contributions to:
Prostate Cancer Research Institute
Attention: Memorials
5777 W. Century Blvd., Suite 885
Los Angeles, CA 90045
This year,
PCRI is
giving tangible thanks
for generous contributions. For each donation of
$100 we receive by January 31,
2003, we will send that donor
a complimentary copy of the
fact-filled book, A Primer on
Prostate Cancer.
It is our way of saying thank
you – and providing you with
more knowledge at the
same time.
Editor:
Review Board:
Charles Bader
Stanley A. Brosman, MD
Mark Scholz, MD
Publisher:
Prostate Cancer Research Institute
Design & Production: Visual Purple Graphics
Photograper:
Linda McCullough
Prostate Cancer Research Institute
5777 Century Boulevard, Suite 885
Los Angeles, CA 90045
Helpline: (310) 743-2110
Phone: (310) 743-2116
Fax:
(310) 743-2113
E-mail: [email protected]
Websites: www.prostate-cancer.org
www.pcri.org
Executive Director: Glenn D. Weaver
E-mail: [email protected]
Board of Directors
Chester A. Swenson, President
Chairman, Marketing & Financial Services Enterprises
Jerome Seliger, PhD, Vice President
Professor of Health Administration,
California State University, Northridge
Barry L. Friedman, JD, Secretary
Attorney
Mark Scholz, MD
PCRI Co-founder
Healing Touch Oncology
Stanley A. Brosman, MD
Pacific Urology Institute
Pacific Clinical Research
Stanley Schoen
Patient
Brian Gauthier
Gauthier Management Company
Jerry Peters
Planned Giving Opportunities
For information on Planned Giving Opportunities, or how to put PCRI in your
will, please contact: Brian Gauthier by phone at (310) 743-2116,
by fax at (310) 743-2113, or by e-mail at www.pcri.org.
The Prostate Cancer Research Institute is a non-profit corporation, exempt from federal income taxes under section 501(c)(3) of the Internal Revenue Code. It has been classified as an organization that is not a private foundation as defined in section 509(a)
of the Code, and qualifies for a maximum charitable contribution by individual donors.
MCG Records
The cost of printing and mailing this newsletter
is made possible through a generous grant from
The Life Extension Foundation
P.O. Box 229120, Hollywood, Florida 33022
Phone: 1-800-544-4440; Website: www.lef.org
The opinions expressed in the by-lined articles are
those of the authors and should not be considered
opinions of the PCRI.
© Copyright 2002. Printed on recycled paper.
15
Conference
continued from page 9
And in the afternoon, there was a
remarkable live demonstration of
Color Doppler and tissue harmonic
ultrasound by Drs. Bahn and Lee.
Three men, whose PSAs that morning gave an indication that they
might have prostate cancer, agreed
to be diagnosed using the new ultrasound equipment.
The procedure was performed backstage and the video was projected
onto a large screen in the auditorium
so that the audience could see exactly how Dr. Bahn used this powerful
tool to look for precise areas where
cancer was located. Rather than performing biopsies without knowing
where the cancer was most likely to
be located, Dr. Bahn next biopsied
the prostate gland in these precise
areas to allow for laboratory confirmation of his diagnosis.
In addition to all this formal presentation of information, many prostate
is published by:
Prostate Cancer Research Institute
5777 W. Century Blvd., Suite 885
Los Angeles, CA 90045
Websites: www.prostate-cancer.org
www.pcri.org
CHANGE SERVICE REQUESTED
cancer patients who
attended the conference
exchanged stories of
their personal battles
with the disease. And it
was clear that the conference had helped them
better understand the
meaning and importance
of the unfamiliar data
their doctors provided.
That may be why so many attendees
are saying, “I’m really glad we went.
When will you have another one?”
The PCRI is already planning the
next conference. This one will be a
national conference
in Washington, D.C.
next fall. We plan to
have it be every bit as
valuable and successful as this regional
western conference
has been.
NONPROFIT ORG.
U.S. POSTAGE
PAID
LIFE EXTENSION
FOUNDATION