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IS PROSTATE CANCER?
is a malignant tumor that arises in the prostate gland. [ See
Box The Prostate Gland, below.
] As with any cancer, if it is advanced or left untreated in
early stages, it can eventually spread through the blood and lymph
fluid to other organs. Fortunately, prostate cancer tends to be
slow growing compared to other cancers. As many as 90% of all prostate
cancers remain dormant and clinically unimportant for decades. This
high incidence of latent or incidental malignancy is unique to the
prostate gland. Most older men eventually develop at least microscopic
evidence of prostate cancer, but it often grows so slowly that,
as one specialist has written, many men with prostate cancer "die
with it, rather than from it."
The Prostate Gland
Description of the Prostate Gland
gland is located between the bladder and the rectum and
wraps around the urethra (the tube that carries urine through
the penis). It is basically composed of three different
area of the prostate that wraps around the urethra is called
the transition zone. The entire prostate gland is surrounded
by a dense, fibrous capsule.
Smooth muscle cells, which contract during sex and squeeze
the fluid from the glandular cells into the urethra,
where it mixes with sperm and other fluids to make semen.
Glandular cells, which produce a milky fluid that liquefies
Stromal cells (which form the structure of the prostate).
Functions of the Prostate Gland
gland provides the following functions:
The glandular cells produce a milky fluid, and during
sex the smooth muscles contract and squeeze this fluid
into the urethra. Here, it mixes with sperm and other
fluids to make semen.
The prostate gland also contains an enzyme called 5
alpha-reductase that converts testosterone to dihydrotestosterone,
another male hormone that has a major impact on the
Changes During the Lifespan
gland undergoes many changes during the course of a man's
life. At birth, the prostate is about the size of a pea.
It grows only slightly until puberty, when it begins to
enlarge rapidly, attaining normal adult size and shape,
about that of a walnut, when a man reaches his early 20s.
The gland generally remains stable until about the mid-forties,
when, in most men, the prostate begins to enlarge again
through a process of cell multiplication.
SERIOUS IS PROSTATE CANCER?
is the most common male cancer in the US. Only lung cancer causes
more cancer deaths in American men. The lifetime probability of
developing prostate cancer is 8%. Each year, approximately 180,000
men in the United States will be diagnosed with prostate cancer,
and about 32,000 will die from the disease. It should be noted that
because older men often die while suffering from both prostate cancer
and other serious medical disorders, official records may attribute
many deaths to prostate cancer that are actually due to other causes.
Some researchers believe that deaths caused by prostate cancer are
misreported (mostly overdiagnosed) by as much as 10% to 20%.
After Early Detection
Because so many
prostate tumors are low-grade and slow growing, survival rates are
excellent when prostate cancer is detected in its early stages.
Cure rates are as high 98%.
After Late Detection
If the disease is at a stage known as locally advanced, in which
it has spread beyond the prostate but only to nearby regions, it
is more difficult to cure, but survival rates can be prolonged for
years in many men. (When cancer has metastasized to the pelvic lymph
nodes, the outlook is worse than if it spread to other areas.)
Metastasized Cancer. If prostate cancer has spread to distant
organs (metastasized), average survival time is one to three years,
but some of these patients may live longer or die of other causes.
If cancer recurs
after initial treatment for early-stage tumors, it is still potentially
curable if it is contained within the prostate, although in most
cases the cancer has spread. Hormone treatments for such recurring
cancers can often prolong survival for years, although the cancer
almost always returns again.
ARE THE RISK FACTORS FOR PROSTATE CANCER?
of prostate cancer rose dramatically between 1976 and 1994, particularly
in younger men, in large part because of early detection with the
use of more accurate screening tests. In determining risk factors
for prostate cancer, a recent analysis of major cancers suggested
that heredity might play a critical role in many prostate cancer
cases. There has been somewhat less evidence for a major role from
lifestyle or other environmental factors in prostate cancer than
in some other major cancers (breast, lung, and stomach).
and Prostate Cancer
It is clear that
hormones play a critical role in prostate cancer, but researchers
have not yet fully clarified the specific hormones that may contribute
to the disease. Some hormones under investigation include the following:
In a 2001 study of 17 hormones, none were associated with prostate
cancer risk except one called androstanediol glucuronide, which
at certain levels suggested a lower risk.
One study found a higher risk with increasing testosterone and a
lower risk with increasing estrogen levels.
Dihydrotestosterone (DHT) is the principal male hormone in the prostate
gland. It affects the size of the prostate gland itself and may
play a role in prostate cancer.
Sex hormone-binding globulin (SHBG) binds to male hormones and leaves
less available to stimulate prostate cell growth. High levels, then,
are associated with protection against prostate cancer.
Insulin-like growth factor-I is a hormone that may increase the
risk for prostate cancer.
occurs almost exclusively in men over the age of 40 and is still
rare until age 50. Almost half of all men under 70 have at least
microscopic prostate tumors. By age 80 to 90, 70% to 90% of men
have evidence of microscopic disease.
and Being African American
men have the world's highest risk for prostate cancer, more than
50% higher than the risk for Caucasian American males. The disease
is also far more lethal among African Americans. A number of factors
may explain these differences.
Socioeconomic Issues. Socioeconomic factors may contribute
to higher mortality rates in African Americans. For example, a 2000
study at a Veterans hospital where all the men had equal care reported
no differences in tumor properties between African American and
Caucasian men. The study suggests that African Americans have no
higher risk for aggressive tumors, and their higher mortality rates
are likely to be due to socioeconomic factors, such as lack of insurance,
irregular screening and a late diagnosis, and unequal access to
health care. Still, biologic factors still appear to play a role
in the ethnic differences for the risk for prostate cancer itself
and possibly in the severity of the cancer. For example, prostate
cancer rates among Native Americans and Hispanic Americans are lower
than those for Caucasians, despite their social and economic disadvantages.
Dietary Factors. Dietary or other environmental factors may
play some small role in ethnic differences. This is suggested by
the fact that, in spite of the high incidence in African American
men, prostate cancer is rare in many parts of Africa. As another
example, when Japanese men move to the US and adopt Western dietary
habits, their risk for prostate cancer increases.
Differences in PSA Results. Research has suggested that African
men may have higher prostate-specific antigen (PSA) levels than
Caucasian men in their own age groups. This suggests that the current
screening standards for PSA levels are less accurate for African
Americans, although a 2001 study suggested that the known differences
are minor and do not yet justify race-specific testing standards.
Insulin-Like Growth Factor Binding Protein (IGFBP3). A study
reported that African American men have lower levels than Caucasian
men of a protein called insulin-like growth factor binding protein
3 (IGFBP3), which may protect against cancer. (Insulin-like growth
factor-I is a hormone that may increase the risk for prostate cancer
in any man.)
History and Genetics
Men with a family
history of the disease have a significantly higher risk of developing
prostate cancer. For a man whose father had prostate cancer, the
risk is about two and one-third times normal. The brother of a prostate
cancer patient may face four and a half times the normal risk of
developing prostate cancer. A number of genes are under investigation.
Some genetic defects are inherited, but other mutations may be acquired
after environmental or biologic assaults over a man's lifetime.
ELAC2. Researchers have identified a gene, called ELAC2,
that may play a role in 2% to 5% prostate cancers. One variation
puts men at moderate risk for prostate cancer and the other at significant
risk (5 to 10 times). .
BRCA2. There is some evidence that mutation of the BRCA2
gene may carry a risk for prostate cancer in men, although in a
very small fraction of patients. (This gene is associated with breast
and ovarian cancers in women.) Previous research has found a higher
risk of prostate cancer among men with a family history of breast
or ovarian cancer, although a 2000 study did not find such a link,
at least with breast cancer.
HPC1. Researchers have identified a gene called HPC1, which
has been associated with 30% of inherited cases. A genetic abnormality
that causes overproduction of a protein called Ret may prove to
be implicated in some prostate cancers.
Androgen Receptor Gene. Variations in the gene that regulates
the receptor for androgen are associated with prostate cancer and
also with changes in PSA levels. They also may help explain some
of the differences in risk between African Americans and other ethnic
Mutations in Tumor Suppressing Genes. Mutations in genes
that ordinarily suppress tumors, such as PTEN and p27, may play
a role in some non-inherited cases.
the relationship between vasectomy and prostate cancer have been
None of the studies
reporting higher rates of prostate cancer in men with vasectomies
can exclude the possibility that they may simply be due to earlier
prostate screening in men who have had vasectomies. Research on
the relationship with prostate cancer is continuing, although if
any link is found, it is likely to be very weak.
- A number
of studies have reported some association between vasectomy
and a higher incidence of prostate cancer. Two of the most recent
ones were Canadian studies in 2000 and 2001. The 2001 study
reported a higher risk beginning 10 years following the procedure.
- A 1999
study that specifically investigated a possible association
between vasectomy and prostate cancer found no link. In fact,
men with vasectomy who did have prostate cancer were more likely
to be diagnosed at an earlier stage and with a less aggressive
Men whose work
involves heavy labor and those exposed to certain metals and chemicals,
including cadmium, dimethylformamide, and acrylonitrile, may be
at higher risk for prostate cancer. Some studies have indicated
that farmers might be at higher risk.
A 2001 study of data collected between 1979 and 1985 concluded that
certain leisure activities may expose men to the same chemicals
as those that pose a possible danger in the industrial setting.
They included the following:
- Home or
stripping, or varnishing furniture
that involve exposure to lubricating oils or greases, metal
dust, or pesticides or garden sprays
a Western lifestyle is associated with prostate cancer, a direct
causal role for either obesity or dietary fats has not been
established. [See What Dietary Factors Are Associated with Prostate
Cancer Risk and Protection?] A 2001 study did find obesity to
be associated with a modest increase in prostate cancer mortality,
although not with the risk for prostate cancer itself. In a
previous study of Chinese men, however, it was not obesity itself
but an unhealthy fat distribution that was associated with a
higher risk. High-risk individuals in the study were those whose
fat was more centered in the abdomen, the so-called apple-shape.
This higher waist-to-hip ratio is also a risk factor for diabetes.
Such findings have led experts to investigate two hormones,
leptin and insulin-that are associated with both obesity and
diabetes. Either of these hormones could theoretically stimulate
prostate cancer growth. In another 2001 study, moderate (not
high levels) of the hormone leptin was linked to prostate cancer,
suggesting that there may be a critical fat mass that is predisposed
to the disease. [ See also Diet under How Can
Prostate Cancer be Prevented, below.]
Factors Associated with Prostate Cancer
Life. A lthough some studies have suggested that an active sexual
life may increase the risk for prostate cancer, most studies refute
this possibility. One study found that the risk for Catholic priests
was no lower than in sexually active men.
Nonmelanoma Skin Cancers and Sunlight. One study reported
that patients with prostate cancer and a history of nonmelanoma
skin have a higher risk for a poorer outlook. Such skin cancers
are highly associated with exposure to sunlight. It should be noted,
however, sunlight triggers production of vitamin D in the body,
which may help protect against prostate cancer. Prostate cancer
rates are, in fact, lower in southern, sunny regions.
Infection. Some association has been seen between prostate
cancer and infections, such as bacterial prostatitis, and some viral
infections, including those caused by herpesvirus, human papillomavirus,
and cytomegalovirus. No link has been proven and a study found no
relationship with papillomavirus. Although some of these agents
are sexually transmitted, the association with sexual activity is
still unclear; one study even found a lower rate of prostate
cancer in men with a history of sexually transmitted diseases.
DIETARY FACTORS ARE ASSOCIATED WITH PROSTATE CANCER RISK AND PROTECTION?
evidence of prostate cancer appears to be similar in men around
the world, its progression differs with location. For example, men
who live in Asia have a lower incidence of clinically apparent prostate
cancer than Asians who move to America. Diet may play some role,
although it is not yet clear if there is any protective diet. It
is important to note that the effects of the foods and food substances
discussed below on prostate cancer risk require further investigation,
and any evidence on their effects is very weak. A major study is
underway to determine the cancer-protective effects of selenium,
vitamin E, and low fat diets.
have found some association between high fat-intake and prostate
cancer. A 1999 study found no association between intake of any
major fats, including saturated (animal fats) and unsaturated fats
(vegetable oils). More intensive research however is investigating
specific fatty acids, compounds that make up fats, which may clarify
the role of fats.
It should be
noted that some dietary intake of all of these fatty acids is important
for health. Research suggests, however, that our current Western
diet contains an unhealthy high ratio (10 to 1) of omega-6 to omega-3
fatty acid, and that a better balance may be beneficial.
Fish and Omega-3 Fatty Acids. Some research has suggested
that omega-3 fatty acids, which are plentiful in dark, oily
fish, may be protective. A study in Sweden found that men who
ate little or none of such fish (e.g. salmon, sardines, halibut,
swordfish, and tuna) were twice as likely to develop prostate
cancer as those who ate two or more servings a week. Omega-3
fatty acids also may combat heart disease, and have shown promise
against cancers of the colon, rectum and ovary.
and Omega-6 Fatty Acids. On the other hand, some research
has indicated that alpha-linolenic acid and total omega-6 fatty
acids may increase the risk of prostate cancer. Sources
of these fatty acids are the polyunsaturated vegetable oils
(e.g., corn, safflower, soybean, canola, and sunflower oil),
which constitute most of the oils consumed in the US.
A number of studies
have suggested that soy may be protective, which may partially explain
the low rate of prostate cancer observed in Japanese men. Soy is
a rich source of an estrogen-like plant compound that has been shown
in laboratory studies to inhibit hormones that promote prostate
Diets high in
fresh fruits and dark-colored vegetables are known cancer fighters.
Specific vegetables that may be particularly important for preventing
prostate cancer include cooked tomatoes, which are high in a beneficial
plant chemical called lycopene, and cruciferous vegetables such
as cauliflower and broccoli. Boron-rich fruits may also be protective.
They include red grapes, avocados, and dried fruits.
Grains and Nuts
Whole grain cereals,
seeds, and nuts appear to be protective. Part of this protection
may be due to their high fiber content. Fiber binds to sex steroids
and is excreted, carrying the hormones with it. Whole grains contain
selenium [ see below ], a rare element that may have some
protective properties. And nuts contain boron, which may also protect
against prostate cancer.
Vitamin D. One 2000 study reported an association between consuming
large amounts of dairy products and a modestly increased
risk for prostate cancer. One possible basis for this finding is
some evidence that calcium (contained in dairy products) can lower
levels of the most active form of vitamin D (1,25 dihydroxyvitamin
D), which may help protect against prostate cancer. In fact, some
research is focusing on prostate treatments using vitamin D analogs.
There is still no clear proof, however, that high calcium and low
vitamin D levels pose a significant risk for prostate cancer.
Vitamin E. A large 1998 trial of male smokers found that
long-term daily use of 50 mg of vitamin E markedly decreased the
incidence and mortality of prostate cancer. It had no protective
effect for men who already had prostate cancer. One major study
suggests the possible benefit of vitamin E is confined strictly
to smokers or recent quitters. Other, more recent studies suggest
that specific natural forms of vitamin E, such as gamma tocopherol
or vitamin E succinate, might have anti-cancer benefits and warrant
more study. (The form of vitamin E in most supplements is dl alpha
tocopherol, a synthetic form.)
Selenium. In laboratory studies, selenium has acted directly
on prostate cancer cells, stimulating cell death and inhibiting
growth. Studies on actual significant protection from selenium supplements
against prostate cancer, however, have been weak. In one study,
men who took a 200 mcg daily supplement had a lower incidence of
prostate cancer. It should be noted that high amounts of selenium
can be toxic, and can cause hair and nail loss.
Zinc. Zinc is of interest because it accumulates to the highest
levels in a man's body in either a normal prostate or one enlarged
from benign prostate hyperplasia. It may be important for prostate
health, although its effects are still not clear.
known as turmeric, is a common yellow seasoning in Indian and other
Southeast Asian countries. Interesting laboratory studies have suggested
that it significantly inhibits the growth of prostate cancer. To
date, however, animal studies have not reported any protection.
Moderate to heavy
alcohol intake (22 to 56 drinks a week) has been associated with
NONDIETARY MEASURES CAN HELP PREVENT PROSTATE CANCER?
Exercise is beneficial
for general health and it temporarily lowers testosterone levels.
Studies on its effects on prostate cancer are mixed. It may not
have much effect on men who are at low risk to begin with. A 1998
study suggested that although exercise had no protective effect
overall on prostate cancer, vigorous exercise was associated with
a lower risk for metastatic prostate cancer. Exercise in any case
is an important component in any health-protective program.
Anti-inflammatory Drugs (NSAIDs)
There is some
evidence from animal studies that nonsteroidal anti-inflammatory
drugs (NSAIDs) have properties that offer some protection against
prostate cancer. NSAIDs suppress chemical in the body called COX-2,
a protein that may cause prostate cancer cells to spread. Standard
NSAIDs include aspirin, ibuprofen (Advil), and naproxen (Aleve,
Naprosyn, Naprelan, Anaprox). More powerful NSAIDs, such as sulindac
(Clinoril) are available by prescription and are being studied for
protection. Newer agents, such as celecoxib (Celebrex), rofecoxib
(Vioxx), and meloxicam (Mobic) only suppress COX-2 and may warrant
specific investigation. Human studies on the protective value of
NSAIDs are weak to date, and they may be helpful only in specific
ARE THE SYMPTOMS OF PROSTATE CANCER?
usually causes no symptoms in the early stages. As the malignancy
spreads, it may constrict the urethra and cause urinary problems.
Later-stage symptoms typically include:
- Weak urinary
in the urine.
of urinary stream (stopping and starting).
urination (especially at night).
- Pain or
burning during urination.
of significant pain in one or more bones may herald the occurrence
of bony metastases. This chronic pain occurs most often in the spine
and sometimes flares in the pelvis, the lower back, the hips, or
the bones of the upper legs. It may be accompanied by significant
OTHER CONDITIONS HAVE SYMPTOMS SIMILAR TO PROSTATE CANCER?
Prostatic Hyperplasia (BPH)
In up to half
of men in their fourth decade, the prostate begins to enlarge through
a process of cell multiplication called benign prostatic hyperplasia
(BPH). The symptoms of BPH can mirror late-stage prostate cancer
because the enlarging inner portion of the prostate puts pressure
on the urethra, which can potentially cause urinary problems. About
80% of men eventually develop enlarged prostates, but only some
experience significant symptoms. BPH is a normal condition and is
not life-threatening. [ For more information,
71, Benign Prostatic Hyperplasia .]
Relationship to Prostate Cancer. Because the prostate enlargement
in BPH is affected by testosterone, many men are concerned that
it may be related to prostate cancer. Fortunately, current evidence
indicates that it has no effect one way or the other. The two conditions
develop in different parts of the prostate. BPH occurs in the inner
zone of the prostate, while cancer tends to develop in the outer
area. A ten-year study found no higher risk for prostate cancer
in men with BPH.
an inflammation of the prostate, often caused by bacterial infections.
Symptoms include urgency, frequency, and pain in urination, sometimes
accompanied by blood in the urine or fever.
TESTS ARE USED TO SCREEN AND DIAGNOSE PROSTATE CANCER?
for Annual Screening
Cancer Society and the American Urological Association (AUA) recommends
annual screening in the following:
screening should start in most men aged 50 to 70. (Based on
a computer model, however, some experts recommend testing all
men at ages 40 and 45 then every two years from age 50 on. Such
a protocol, the model suggests, would be more cost effective
and prevent more deaths than the current screening schedule.)
- Most experts
agree that men with a family history of prostate cancer and
all African-American men should start screening at about age
Screening Tests for Early Detection
standard tests are used for early detection of prostate cancer:
PSA is currently
considered the best single test for early prostate cancer detection,
although the DRE will sometimes detect tumors in patients who have
normal PSA levels. There is considerable controversy, however, surrounding
the value and accuracy of these tests for early detection of prostate
cancer. [ See Box Accuracy of Screening Tests.]
- A digital
rectal exam (DRE), in which a physician palpates the prostate
in order to feel lumps or masses.
- A blood
test that measures the level of a protein produced in the prostate
known as prostate-specific antigen (PSA).
If the digital rectal examination indicates the presence of cancer,
regardless of the PSA results, a physician may also obtain a visual
image of the prostate through an ultrasound procedure called transrectal
Only a biopsy, however, in which a tiny sample of prostate tissue
is surgically removed, can actually confirm a diagnosis of prostate
cancer. Other tests are being developed, such as the so-called free
PSA test, that may improve accuracy.
Rectal Exam (DRE)
About 90% of
all prostate cancers arise in the outer part of the prostate where
they may be detected by a digital rectal exam (DRE), which is the
simplest and most widely-performed screening procedure. The doctor
inserts a gloved and lubricated finger into the patient's rectum
and feels the prostate for bumps or other abnormalities. The exam
is quick and painless but some men find it embarrassing. It is not
very accurate in detecting early cancers but studies indicate that
regular DREs still save lives. [ See Box Accuracy
of Screening Tests.]
PSA is a protein
produced in the prostate gland that keeps semen in liquid form.
Prostate cancer cells appear to produce the protein in elevated
quantities. Measuring PSA levels, then, increases the chance for
detecting the presence of cancer when it is microscopic. Elevated
or reduced levels of PSA can be used for guidelines only, however.
The test is not accurate enough to either completely rule out or
confirm the presence of cancer. [ See Box Accuracy
of Screening Tests.]
Factors Affecting Accuracy. A number of factors and noncancerous
conditions can influence PSA levels:
Even with its
limitation, the PSA test has increased the number of detectable
early-stage and therefore treatable cancers. In one study, centers
reported that between 1987 to 1995 cancers detected in very early
stages increased from 2.1% to 36.4%, while advanced cancer rates
declined from over 25% to under 6%. Because of the slow-growing
nature of prostate cancer, however, it is not known whether all
of these very early cancers will result in significant or life-threatening
Normal levels in Caucasian males may be different from those
for African-American or Asian men. Some experts believe that
there should be different scales for determining risk among
these groups, but there is still not enough information to support
a specific range for various ethnic groups.
- Age. PSA
levels tend to rise naturally with age, so an elevated level
in a man who is 70 may be less serious than the same level in
a younger man. Some experts believe that men over 65 years old
who have low PSA levels are at such low risk for prostate cancer
that they may be able to forego further testing.
Prostatic Hyperplasia (BPH) and Its Treatments. Between 25%
to 56% of patients with BPH have elevated levels. Certain surgical
treatments for this condition can also elevate PSA. On the other
hand, the drug finasteride (Proscar) may reduce PSA levels,
so that cancer might be missed.
About half of men with elevated PSA levels but no signs of cancer
on biopsy have signs of prostatitis as indicated by urine and
prostate secretion tests. (Prostatitis simply means inflammation
in the prostate. Inflammation is usually due to bacterial infection
but it can also be caused by nonbacterial factors.) In one study,
screening for prostatitis increased the accuracy of the PSA
test significantly and reduced the number of unnecessary biopsies.
Noncancerous Conditions. Other noncancerous conditions that
can increase PSA levels include surgical procedures for BPH,
acute urinary retention, digital rectal examinations (DREs),
and prostate biopsies themselves.
Ejaculation within 48 hours can raise PSA levels, although one
study suggested that this occurs only when PSA levels were already
PSA Tests and Effects on Mortality Rates. It is not yet
confirmed that PSA tests actually save lives, although studies are
promising. Deaths from prostate cancer, for instance, have declined
in the US and European countries where screening is common, which
might be due to earlier diagnoses and treatment at localized stages.
Such studies, however, lack confirming evidence that these reductions
in mortality rates are directly due to early screening or to other
factors, such as improvements in risk factors. Moreover, prostate
cancer death rates have also declined in England and Wales, where
PSA screening is not widely practiced. In addition, while early
detection has increased cancer diagnosis by about 80 per 100,000
men in the US, the death rate has declined by only 4 per 100,000
and is still greater than in the 1970s and 1980s.
To improve the
accuracy of the PSA tests, particularly when PSA levels fall between
4 and 10 ng/mL, researchers are developing methods for measuring
other factors. To date, no test has emerged as clearly superior
to the PSA test.
Free PSA Test. A small amount of prostate specific antigen
leaks out of the prostate into the bloodstream. There, PSA can circulate
without bonding and is referred to as free PSA. It can also form
chemical combinations with other proteins. If cancer is present,
PSA is more likely to be bound, and so there is less free PSA in
circulation. The free PSA blood test, then, is a ratio of free PSA
to the total PSA (free PSA plus chemically bound PSA).
The following results are used to determine the presence or absence
A 2000 report
suggested that testing free PSA may improve prostate cancer detection
by roughly 40%. In addition, any cancers that the test missed would
not develop into significant disease for at least nine years, providing
ample opportunity to identify them before they became serious. Not
all studies support its advantages over total PSA, however. For
instance, a 2001 study compared repeated screening tests using total,
free, and complexed PSA [ see below ]. Its results suggested
that total PSA was more accurate in predicting prostate cancers
than the other two.
- A free-to-total
PSA ratio of 20% or lower plus total PSA levels of 4 to 10 ng/mL
are strongly suggestive of prostate cancer. (Some experts use
25% as a cut-off, but studies suggest that using this cut-off
would miss cancers in many African American and older men.)
- A free-to-total
PSA level of over 20% plus normal or even moderately elevated
total PSA are more likely to indicate the presence of other,
benign conditions, such as benign prostatic hyperplasia.
Complexed PSA Test. Complexed PSA (cPSA) is a form of circulating
PSA that is bound to a molecule termed alpha1-antichymotrypsin.
It represents about 90% of the total PSA in men and is significantly
higher in men with prostate cancer than in those with BPH. To date,
studies have reported conflicting results on its benefits for diagnosing
procedure called transrectal ultrasonography (TRUS) provides a visual
image of the prostate and is used if the DRE indicates the presence
of cancer. Ultrasound is not effective as a diagnostic tool by itself
because it cannot differentiate very well between benign inflammations
and cancer, but the procedure may help to confirm an uncertain preliminary
diagnosis and is useful as a guide for needle biopsies. Ultrasound
enhancements, such as Doppler imaging or computer modeling techniques
called artificial neural networks (ANN), may increase the accuracy
for Biopsy and Follow-Up
would consider performing a biopsy to confirm a diagnosis of prostate
cancer after screening tests report the following results:
however, are not cut in stone. In most cases, abnormal levels do
not mean that a man has cancer and normal levels do not always mean
a man is cancer-free. For example, biopsies in the majority of men
with elevated PSA levels show no cancer after biopsy. (This does
not necessarily mean these men are cancer-free. Biopsies, too, can
miss cancers, particularly when tumors are very small.) A 2000 study
concluded that the best indicator for a biopsy was a combination
of a positive PSA and DRE result in an older man, rather than any
one test taken alone. And, there is some evidence that each test
may detect cancers that the other doesn't. Researchers in a major
European study, however, are recommending biopsies without
a DRE for PSA readings of 3 ng/ml and above. [ See Box Accuracy
of Screening Tests.]
- PSA level
of 4.0 ng/mL or higher.
- PSA level
that has increased significantly from one test to the next.
digital rectal examination (DRE).
Between 85% and 92% of men have PSA levels below 4.0. In such cases,
some experts recommend follow-up in these cases:
- DRE and
PSA screening every three years for PSA levels lower than 1.0
ng/ml. (DRE at these levels are more useful than PSA in detecting
PSA screening for levels 1.0 to 3.0 ng/ml.
of Screening Tests
Risk of Cancer with Abnormal Results
About 2% or less chance of cancer for readings below 3 ng/ml.
Between 17% and 50% chance of cancer for readings 3 to 10
Very strong chance above 10 ng/ml.
Less than 20% chance for cancer with abnormal results. Unfortunately,
up to 70% of cancer detected with DRE alone have already
spread beyond the prostate gland.
Over 60% chance for cancer with abnormal results.
Risk of Missed Cancers with Normal Results
Between 9% and 37% of prostate cancers are present in men
with PSA levels below 4 ng/ml and no indications from a
About 60% of cancers are missed.
If preliminary tests raise the suspicion of cancer, physicians
will perform a biopsy. Biopsy is used to diagnose prostate cancer,
and is a very accurate method for predicting the severity of an
More than half
of the men who have a biopsy experience discomfort and anxiety,
with men under 60 reporting higher levels of discomfort than older
men. Taking a sedative an hour or two before the procedure can help
reduce distress. Complications of biopsy are low, but urinary tract
infection, fever, or bleeding occurs in 0.1 to 4%.
- Core Biopsy.
The standard method is called a core biopsy, which uses a spring-loaded
biopsy device inserted into the rectum. The device propels a
needle into the prostate, obtaining a core of tissue, which
is examined by pathologists.
- Fine Needle
Aspiration. A more recent procedure called fine needle aspiration
is less painful and may be as accurate as a core biopsy if the
sample obtained is sufficient for analysis and if it is analyzed
by a skilled pathologist.
Repeat Biopsies. Because a biopsy can miss very small cancer
cells, sometimes three or even more biopsies are recommended if
PSA levels are very high. Repeat biopsies are indicated if initial
results do not detect any cancer but any of the following are true:
In a 2001 study,
in men with PSA levels of 4 to 10 ng/mL who did not show signs of
cancer on the first biopsy, the following cancer rates were reported
on subsequent biopsies:
- PSA levels
are abnormally high. One study suggested that patients with
free PSA less than 30% or transition zone PSA density of 26%
or greater should have repeat biopsies. (Free PSA was the most
accurate predictor of prostate cancer for repeat biopsy patients.)
- DRE results
are abnormal [ see above ].
results are abnormal [ see above ].
- The initial
biopsy yields microscopic findings that are suspicious.
- The initial
biopsy detects precancerous cells known as high-grade prostatic
intraepithelial neoplasia (PIN). No treatment is necessary with
this finding, but these patients should be rechecked every three
to six months for the next two years, and then annually.
The cancers found
in biopsies 3 and 4 tended to be nonaggressive with favorable outlooks.
biopsy: 10% cancer rates.
Zone PSA Test. Some tests have been developed to measure the
density of the PSA in the transition zone of the prostate
gland. (The transition zone is the central area of the prostate
that wraps around the urethra, the tube that carries urine down
through the penis.) One study reported that a PSA density of 35%
predicted prostate cancer in 90% of cases. A combination of free
PSA and transition zone PSA may be particularly useful.
Human Glandular Kallikrein 2 (hK2), Human glandular kallikrein
2 (hK2) is a chemical cousin of PSA. HK2 testing seems to do a better
job than testing for total and free PSA for discriminating between
cancers that are confined to the prostate and those that have spread
to other locations.
Urine Test for Hypermethylation. A condition known as hypermethylation
is an early genetic change that occurs in 90% of prostate cancers.
Hypermethylation is caused by the glutathione-S-transferase (GSTP1)
gene and it is not found in normal cells or in men with benign prostatic
hypertrophy (BPH). Tests to detect this condition are in development.
Tests for Insulin-like-Growth Factor. Insulin-like growth
factors have been implicated as possible triggers of cancer cell
growth. Levels of these growth factors may provide information on
future cancer risks, particularly in African American men. More
research is needed in this area, however.
TESTS INDICATE THE EXTENT OF EXISTING PROSTATE CANCER?
Once cancer is
diagnosed, PSA levels may help to determine its extent. If PSA levels
are less than 20 ng/ml, then it is possible that the cancer has
not spread to distant sites. PSA levels over 40 ng/ml is a strong
indicator that cancer has metastasized (has spread to sites that
are distant from the origin, in this case the prostate gland). PSA
levels are also monitored after initial treatments for prostate
cancer. Rising levels indicate recurrence, although the cancer may
not recur for a long time, and the location of the new cancer cannot
be determined using PSA testing. Measuring the free PSA percentage
before surgery may prove useful for determining outcome. One study
indicated that the higher the percentage, the less aggressive the
disease. [ For more details, see What Tests Are Used to
Diagnose Prostate Cancer? , above .]
A number of biological
factors are being used or investigated as markers for cancer or
Chromosomal Sets. The number of chromosomal sets in the nucleus
of the tumor's DNA, known as its ploidy, is an important marker
for patients in late stages of prostate cancer. Tumors with the
normal two sets of chromosomes, called diploid tumors, usually have
a more favorable outcome than tumors that have four sets of chromosomes
(tetraploid tumors) or have an abnormal number of individual chromosomes
Blood Vessel Density. The density of blood vessels in the
tumor is an important indicator of outcome. The greater the density,
the more likely the tumor is to be aggressive.
Testosterone Levels. Higher total testosterone levels may
increase the risk for metastasis. A 2000 study found an association
with low free testosterone and more extensive prostate cancer,
suggesting it could be a marker for aggressive disease. (Free testosterone,
as with free PSA, is not chemically bound.)
Other Markers, Other markers being investigated for predicting
cancer progression include prostate-specific membrane antigen,
prostatic acid phosphatase, growth factors, and genes that regulate
tumor growth (eg, p53, p27, bcl-2).
is a scanning technique that uses tiny amounts of radioactive material
with a monoclonal antibody that can attach specifically to prostate
cancer cells. A special camera then can detect tumor cells that
cannot be detected with other diagnostic tools. It may be effective
in helping physicians make better treatment decisions. In a 2000
study, 90% of patients who underwent ProstaScint scanning had a
successful treatment outcome (determined by normal or below normal
PSA levels) compared to 60% of patients who did not undergo scanning.
The role of this test in the routine management of prostate cancer
is still being defined.
If the biopsy
indicates cancer, the physician will order other tests to determine
whether or how far the cancer has spread.
Bone Scans and X-Rays. Bone scans and x-rays may reveal whether
the cancer has invaded the bones. To perform a bone scan, physicians
inject low doses of a radioactive substance into the patient's vein,
which accumulates in bones that have been damaged by cancer. A scanner
then reveals how much of the radioactive material has accumulated.
Arthritis and infections may also produce positive scans. Patients
with PSA levels below 20 ng/mL are unlikely to have scans that show
cancer in the bone.
Computed Tomography and Magnetic Resonance Imaging. Computed
tomography (CT) or magnetic resonance imaging (MRI) scans can further
pinpoint the location of cancer that has spread beyond the prostate.
Bone Metastasis Markers. Researchers are investigating chemical
markers, such as a amino-terminal propeptide of type I procollagen
(PINP), as early indicators of bone metastasis.
ARE PROSTATE CANCER TUMORS STAGED AND GRADED?
continually searching for methods to determine how aggressive individual
prostate cancers are so they can choose the best treatments. As
an aid, experts have devised different classification systems that
help assess the properties of the cancer. These systems include
staging and grading the tumors and measuring PSA levels. In general,
the higher the stage, grade, and PSA numbers, the more severe the
condition and the more aggressive the treatment. Current classifications
systems have significant limitations in guiding treatment choices.
Newer tests, markers, and imaging techniques may eventually improve
the accuracy of staging categories.
A tumor's stage
is an indication of how far it has spread from its original site.
Cancers are staged according to whether they are still localized
(remain surrounded by healthy cells) or have spread beyond the original
site. Two prostate cancer staging systems are commonly used: the
TNM system and the Jewett system. To avoid confusion, this report
only uses the TNM system. The TNM system is explained in detail,
and the Jewett system is explained in reference to the TNM system.
TNM Staging System
The TNM system
refers to clinical tumor stages as:
- _ T for
- _ N for
regional lymph nodes.
- _ M for
metastasis (tumors developing outside the prostate).
T followed by
numbers 0 through 4 refers to the size and extent of the tumor itself.
The tumor cannot be felt or seen using imaging techniques.
Cancer cells are incidentally found in 5% or less of tissue
samples from prostate surgery unrelated to cancer.
Cancer cells found in more than 5% of samples.
Cancer cells identified by needle biopsy, which is performed
because of high PSA levels.
The cancer is confined to the prostate but can be felt as
a small well-defined nodule.
Tumors are in half a prostate lobe.
Tumors are in more than half a lobe.
Tumors in both lobes.
The tumor extends through the prostate capsule.
The tumor is fixed to or invades adjacent structures.
N followed by
0 to 3 refers to whether the cancer has reached the regional lymph
nodes, which are located next to the prostate in the pelvic region.
Regional lymph nodes are still cancer-free.
A small tumor is in a single pelvic node.
A medium-size tumor is in one node or small tumors are in
A large tumor is in one or more nodes.
M stages refer
to metastasis (tumors developing outside the prostate).
Metastasis has not occurred (cancer has not spread beyond
the regional lymph nodes).
Cancer has spread to lymph nodes beyond the regional lymph
Cancer has invaded the bones.
Cancer has spread to other sites.
Jewett Staging System
The stages in
the Jewett system are roughly equivalent to the stages in the TNM
system as follows:
N1, N2, N3, M1
Gleason Grading System
Tumors are graded
according to a scale known as the Gleason system, which measure
how well or poorly organized they are under the microscope. Two-thirds
of prostate cancers have a mix of tumor grades. The cancer is then
scored by adding the totals of the primary tumor grades.
a prognosis, the tumor grades are then added together for a final
score. For example, a tumor with primarily 3 and 4 grade tumors
is given a score of 7. The following scores are often used to suggest
how well or poorly the tumor is differentiated. The higher the score,
the more severe the break-down of their cellular structure and the
more likely they are to spread aggressively:
1: Single, well-packed tumors.
2: Single, more loosely arranged and less uniform tumors.
3: Single tumors of different sizes and patterns, with cellular
breakdown becoming increasingly worse.
4: Irregular tumor masses, fused together. May show clear cells.
5: the tumors have broken down and cellular structure has markedly
2-4: Well-differentiated. Indicates about a 95% chance for surviving
15 years without aggressive treatment.
5-6: Moderately well differentiated. Slightly lower chance of
survival that decreases with time.
7-10: Moderately poorly to poorly differentiated. 15-year survival
rates of 15% to 40%.
ARE THE TREATMENT OPTIONS FOR PROSTATE CANCER BY GRADING AND STAGING
devised treatments based on classification systems, including staging
and tumor grade.
N0, M0, G1, Stage A. Treatment Options. Watchful
waiting, with hormone treatment if symptoms develop. Surgery (radical
prostatectomy or cryosurgery). Radiation treatment (either external-beam
irradiation or interstitial implantation in selected patients).
For reducing mortality rates, no strong evidence supports one treatment
choice over another; survival rates appear to be equivalent and
close to normal. Treatment may be considered in men under 60, particularly
those with tumors classified as T1b, in which cancer cells are found
in more biopsy samples than in T1a. Postoperative radiation treatment
may be considered if surgery reveals high risk for recurrence. Radiation
with hormone therapy is under investigation for intermediate and
N0, M0, G2, 3, or 4. Treatment Options. Watchful
waiting in selected patients (such as those with low-grade tumors).
Surgery (radical prostatectomy usually with pelvic lymphadenectomy)
or radiation therapy (external-beam irradiation or interstitial
implantation in selected patients). Radiation treatment after prostatectomy
may be considered to reduce local recurrence.
Tumors: T2, N0, M0, Any G, Stage A2, B1 or B2. Treatment
Options. Careful watchful waiting in selected patients (such
as those with low-grade tumors) followed by hormone treatment when
symptoms occur. Radical prostatectomy or radiation treatment (external-beam
irradiation or interstitial implantation in selected patients).
Treatments have similar results for up to 10 years. Possible use
of hormone therapy with radiation treatment. Cryosurgery under investigation.
Neoadjuvant hormonal therapy followed by radical prostatectomy under
N0, M0, Any G (Stage C), Treatment Options. External-beam
irradiation using a linear accelerator is a commonly used treatment
for most of these patients. Hormonal treatment (orchiectomy or androgen-suppressing
drugs) along with radiation may improve survival rates from prostate
cancer. Hormonal treatments alone. Clinical trials using other therapies.
Careful observation in selected patients. (One study reported that
in selected patients with low-grade tumors who chose watchful waiting,
survival rates were 88% at five years and 70% at nine years.) Radical
prostatectomy usually with pelvic lymphadenectomy considered in
highly selected patients but, in general, surgery has very inferior
results compared to radiation.
for Urinary Tract Symptoms. External beam radiation therapy.
Hormonal manipulation. Transurethral resection of the prostate
(TURP). Investigative radiation therapy using protons or neutron
radiation. Investigative cryosurgery.
N0, M0, Any G; or any T, N1 through 3, M0, Any G; (stage D1 or D2)
Treatment Options. Hormonal therapy, which may
be one of the following: orchiectomy alone or with an antiandrogen;
LHRH agonists, such as leuprolide; leuprolide plus an antiandrogen;
estrogens. External-beam radiation possibly used with on-going androgen
suppression treatment for attempted cure in highly selected MO patients.
Radical prostatectomy with immediate orchiectomy under investigation.
Systemic chemotherapy under investigation. Clinical trials using
other therapies. Cure is rare in these patients but striking subjective
or objective responses to treatment occur in many patients.
T, any N, M1, Any G (stage D2). Treatment Options. Hormonal
therapy, which may be one of the following: orchiectomy alone or
with an antiandrogen; LHRH agonists, such as leuprolide; leuprolide
plus an antiandrogen; estrogens. Cure is rare in these patients
but striking subjective or objective responses to treatment occur
in most patients.
for Urinary Tract Symptoms. External beam radiation therapy.
Hormonal manipulation. Transurethral resection of the prostate
(TURP). Investigative radiation therapy using protons or neutron
radiation. Investigative cryosurgery.
Relief. Low dose prednisone (a corticosteroid) alone or
with mitoxantrone (a chemotherapy agent) reduces inflammation
and may help relieve pain.
for Urinary Tract Symptoms. External beam radiation therapy.
Hormonal manipulation. Transurethral resection of the prostate
for Symptoms of Bone Metastasis. R adiation therapy (external
beam radiation or strontium-89 radioisotopes) or hormonal manipulation
(orchiectomy or LHRH agonist drugs or both).
Relief. Low dose prednisone (a corticosteroid) alone or
with mitoxantrone reduces inflammation and may help relieve
Options. Dependent on various factors: prior treatment,
site of recurrence, coexistent illnesses, and individual patient
whose cancer recurs locally after prostatectomy: radiation therapy,
whose cancer recurs locally after radiation therapy: hormonal
therapy, prostatectomy (very select patients).
whose recurrent cancer has spread see treatment options for
ARE THE GUIDELINES FOR TREATING LOCALIZED PROSTATE CANCER?
for Choosing the Best Treatment for Localized Cancer
best treatment for localized prostate cancer (T1 or T2) is generally
based on the patient's age, the stage and grade of the cancer, and
the patient's knowledge and acceptance of the risks and benefits
of each therapy.
Patients have three main options:
of Classification System, The classification systems are not
perfect. For instance, even if tumors are rated in low stages and
grades and are treated accordingly, undetected cancer cells may
escape and spread beyond the prostate. [ See What are the
Treatment Options for Prostate Cancer by Grading and Staging Categories?]
Other factors, such as the man's age and medical condition, must
be included in determining whether aggressive treatments or conservative
measures are appropriate.
(radical prostatectomy or cryosurgery) removes or destroys the
prostate gland. The vessels that carry semen and surrounding
tissue may also be removed. With cancer that has spread beyond
the prostate, the pelvic lymph nodes are removed.
is used to destroy tumors.
waiting (for selected patients only) involves lifestyle change
and careful monitoring to see if surgery or radiation becomes
- even the
medical community is divided over the best treatment for localized
prostate cancer. No treatment appears to have a survival advantage.
The choice is often not an easy one, even for experts, for many
- of Data
on Survival Rates. No studies to date have provided evidence
strong enough so that patient and physicians can make confident
choices between watch-and-wait and aggressive treatments. In
general, no approach has emerged with a survival advantage.
In the United Kingdom, radiation therapy is the most common
treatment and mortality rates are similar to those in the US
where surgery is the standard approach. In Sweden, watchful
waiting is the most often chosen option and one study suggested
that their mortality rates declined in parallel with a decline
in aggressive treatments. However, experts argue that the biopsy
techniques used in Sweden are more likely to result in false
diagnoses of prostate cancer and the men in the study tended
to be older than in other studies. A major well-designed study
is underway to help resolve these questions.
Specialty Bias. Patients should be aware that physicians
may be biased to prefer a specific treatment depending on their
specialty. For example, in one study the following treatments were
favored for patients who were generally appropriate candidates for
either surgery, radiation, or watchful waiting:
of the physicians recommended watchful waiting. When in doubt, patients
should always seek a second opinion to help them make this important
- 93% of
urologists recommended radical prostatectomy.
- 72% of
radiation oncologists recommended radiation. (And 82% thought
that radical prostatectomy was overused.)
Quality of Life. Surgery and radiation both have potentially
distressing side effects, including the possibility of impotence,
incontinence, or both. A man must then weigh his own emotional responses
to the possibility of these side effects versus the possible stress
of watchful waiting.
In general, differences in quality of life after surgery or radiation
treatment have to do with the specific effects of each type of treatment.
Studies report the following:
generally causes more bowel problems than surgery does, 30%
to 35% versus 6% to 7%, according to a 2001 study. In the same
study, radiotherapy patients reported more physical and emotional
limitations, although they tended to be older than the surgical
patients. In another 2001 study, however, patients who underwent
external radiation reported no significant decrease in quality
of life throughout the study, which extended to a year after
treatment. Those who underwent brachytherapy (radiation implants)
reported a reduced quality of life during the first three months,
but it returned to normal within a year.
causes more urinary incontinence (39% to 49% versus 6% to 7%
for radiotherapy patients) and more incidences of erectile dysfunction
(80% to 91% versus 41% to 55%), according to a 2001 study. In
another study in the same year, patients who underwent radical
prostatectomy reported lower quality of life during the first
month but it returned to normal by three months.
waiting imposes an emotional burden on any man who must live
with the possibility of progressive cancer and its difficult
treatments. Many who decide to wait become what some physicians
refer to as the "walking worried," men who are constantly concerned
with their PSA levels. Because aggressive treatment reduces
such anxiety, some studies reported that years after surgery,
about three quarters of men say they would chose it again, in
spite of significant side effects, which include impotence and
incontinence in many of them.
involves lifestyle change and careful monitoring to see if surgery
or radiation becomes necessary. Most patients should have a digital
rectal exam and PSA blood test every six to 12 months. If PSA levels
rise, more intensive tests are required to determine if the cancer
has advanced. Patients should exercise and eat healthy foods. [
See What Dietary Factors Are Associated with Prostate Cancer
Risk and Protection?] Symptoms such as weight loss, pain, urinary
problems, fatigue, or impotence should be reported to the patient's
Candidates. Watchful waiting is a consideration for the following
cancer grows so slowly, it is likely that good candidates will die
first from causes unrelated to the cancer. There is therefore little
potential benefit from surgery or radiation, which both pose a risk
for impotence and incontinence.
- Men in
their late 70s and older. More aggressive therapies (surgery
and radiation) are usually recommended for men in their 50s
and younger. The choice for men in their 60s and early 70s is
more problematic. The general recommendation at this point is
that aggressive therapy is suitable for those who have a life
expectancy of more than ten years and who have early and low-grade
cancer. At this point the tumor grade is the best guide for
determining the risks in choosing watchful waiting.
men with early-stage (T0 to T2) low-grade tumors.
- Men with
low to moderate PSA levels.
Surgery (Radical Prostatectomy)
In men whose
cancer is confined to the prostate, surgical resection (radical
prostatectomy) offers the potential for cure. Cure rates from initial
surgery in men with localized cancer are about 70%, depending on
tumor stage, tumor grade, and PSA levels.
Candidates. Radical prostatectomy is a consideration for
men who meet all of the following criteria:
is more likely to cause incontinence (up to 50%) and impotence (as
high as 90%) than radiation treatment but has fewer bowel complications.
Surgery for prostate cancer may be particularly difficult in men
who have had transurethral resection of the prostate (TURP).
- In good
health and with a life expectancy of 10 years or more. As average
life expectancy in men has increased, more older men are becoming
candidates for surgery. Complication rates are higher the older
a man is, however.
- The cancer
has not spread beyond the prostate gland.
- The cancer
is potentially life-threatening. (In general, a life-threatening
tumor is indicated by volumes more than 0.2 cc and Gleason grade
scores greater than 5.)
(or radiotherapy) is administered as external-beam radiation or
as brachytherapy (radiation implants). It may be used as the sole
primary treatment for localized prostate cancer, and has five-year
survival rates similar to those of surgery.
Candidates. Radiation is a consideration for men with one
or more of the following characteristics:
older and, particularly, having other medical problems.
- The cancer
may have extended beyond the prostate capsule but has not spread
to the lymph nodes or further.
a good surgical candidates, but having decided against an operation.
- risk for
impotence (about 50%) and incontinence (less than 10%) is much
lower than with surgery, although bowel problems occur in about
a third of patients.
in prostate cancer uses drugs or surgery (orchiectomy) to suppress
or block male hormones (androgen), particularly testosterone and
Hormonal Treatments for Local Cancer. Investigators are evaluating
a hormonal approach called triple androgen blockade that might prove
to be useful for local or locally advanced prostate cancer. It consists
of an LH-RH agonist (leuprolide or goserelin), an antiandrogen (flutamide
or bicalutamide) and finasteride
Hormonal Treatment After Surgery for High-Risk Patients. Hormonal
treatment may be useful after surgery in men who have high-grade
tumors or tumors that have invaded the semen-carrying vessels or
lymph nodes. Such men have a risk for failure after surgery of 50%
Hormonal Therapy Before Radiation. Hormonal drugs combined
with or used before radiation therapy (called neoadjuvant therapy)
are under investigation and may improve survival rates in moderate-
or high-risk groups. Neoadjuvant therapy may be helpful in shrinking
enlarged glands to that brachytherapy (radiation implants) can be
ARE THE OPTIONS IF LOCALIZED TREATMENTS FAIL?
of Persistent Cancer after Initial Treatment
Levels. If prostate cancer has been eliminated, PSA levels should
drop to 0.5 or less after treatment. A sudden rise or persistently
elevated PSA levels after treatment are often indications that prostate
It is common for PSA levels to temporarily rise following radiation
seed implantation without signaling cancer recurrence.
- If PSA
levels are above 2, then cancer is most likely still present.
- If PSA
levels are between 0.5 and 2, the situation is less clear. One
study indicated that measuring free PSA may help determine the
status of the cancer in such patients. An average free PSA of
27% indicated that cancer had been eliminated, while an average
of 15% meant that cancer was still present.
Prognosis with Recurrence or Failure
Rising PSA levels
do not necessarily mean that the cancer has spread or even that
the cancer will recur during a man's lifetime. An actual cure is
still possible if the cancer is localized within the prostate. In
one study, 64% of patients with rising PSA levels after surgery
still had cancer confined to the prostate. Indications of a poorer
outlook in this study included the following:
the men in the study, after seven years only 3% of patients had
actually died of prostate cancer. After fifteen years, only 19%
had evidence of recurrence. Other markers for persistent cancer
are under investigation. For example blood tests that show low levels
of acid phosphatase (ACP) before treatments may predict a higher
chance for recurrence-free survival.
penetration of the prostate capsule.
surgical margins (microscopic evidence of cancer cells at the
very edge of the resected specimen.
of nearby vessels or lymph nodes.
Hormonal therapy (drugs or surgery that block male hormones)
is often the appropriate response to rising PSA levels after treatment
failure. Some studies suggest that patients given hormonal drugs
may live significantly longer if treatment is started as soon as
PSA levels rise, even if no symptoms occur. Other studies indicate
there is no increased survival from early treatment, and patients
have a better quality of life if therapy is started only after symptoms
Chemotherapy. Chemotherapy agents in combination with hormonal
agents are being investigated for patients who fail surgery or radiation.
(Chemotherapy alone does not appear to offer any benefits.)
Salvage Prostatectomy. Salvage prostatectomy is sometimes
performed after unsuccessful radiation treatment if the cancer is
still local. The odds of the procedure's success are only 10% to
64%. Many experts recommend against salvage prostatectomy in most
cases of radiation failure.
Severe complication rates for salvage prostatectomy are very high:
ten times that of men who have not had radiation. Potential complications
after salvage prostatectomy is often untreatable with medications,
collagen implants, or other standard treatment measures. [ See
What Are the Surgical Treatments for Prostate Cancer?, below.]
- Need for
Salvage Cryosurgery. Salvage cryosurgery may be effective
in certain patients who fail external beam radiotherapy. The best
candidates are those with Stage II cancer or less and PSA levels
below 10 ng/mL.
Adjuvant and Salvage Radiation. Radiation is proving to be
beneficial in patients who still show detectable levels of PSA after
surgery (generally 2 ng/ml or less), and may even be useful years
after surgery if PSA levels rise. Depending on timing, radiation
after treatment failure is referred to as follows:
One area of controversy
is whether to use adjuvant radiation after surgery on patients whose
PSA levels are very low or undetectable but who have other test
results that indicate that the cancer is likely to spread. For example,
analysis of tissue taken during surgery can indicate that the tumor
extends outside the prostate capsule. One study reported that when
such patients were given adjuvant radiation, they had significantly
higher rates of disease-free survival than those who had salvage
radiation. Only a minority (20% to 30%) of these patients experienced
treatment failure, particularly if they had low to moderate Gleason
grade scores. Patients with adverse findings and low PSA have to
weigh the potential complications of radiation therapy against the
odds of recurrence without it, which are about 20% to 30%.
radiation is radiation therapy performed within 6 months of
radiation is radiation therapy more than 6 months after surgery.
ARE THE GUIDELINES FOR TREATING ADVANCED AND METASTASIZED PROSTATE
The primary goals
of late-stage cancer treatments are to:
include the following:
- Slow cancer
treatments used to suppress or block androgens (male steroid
hormones) are the mainstay treatment for advanced and metastasized
cancer (Stage IV).
beam irradiation is used for late stage patients and is the
mainstay for controlling pain caused by metastasis. External-beam
radiation used with on-going androgen suppression treatment
is being investigated for advanced cancer that has not yet metastasized.
[ For more information, see What Are the Radiation Treatments
for Prostate Cancer?, below.]
- One study
has suggested that combinations of certain standard chemotherapy
drugs may be useful for patients with advanced prostate cancer
who fail hormonal treatments. In this study, after one year,
77% of the patients were alive.
prostatectomy is rarely helpful.
Therapies: Blocking Androgens (Male Hormones)
is the mainstay for advanced and metastasized prostate cancer. Hormonal
therapies (drugs, surgery, or both) are used to suppress or block
male steroid hormones, called androgens. Androgens, particularly
testosterone and dihydrotestosterone, determine male secondary sex
characteristics and stimulate prostate cell growth. When prostate
cells, both healthy and cancerous, are deprived of androgens, they
no longer proliferate and eventually die.
Standard Hormonal Treatments. Surgery to remove the testicles
(orchiectomy), hormonal drugs, or both are standard hormonal treatments.
Because orchiectomy is irreversible, about 75% of patients with
advanced prostate cancer choose hormonal therapy to block androgens.
Drugs. The primary agents used for suppressing androgens are
called luteinizing hormone-releasing hormone (LH-RH) agonists.
Orchiectomy is the surgical removal of the testicles. It is
the single most effective method of reducing androgen hormones.
Orchiectomy plus radical prostatectomy may delay progression
in patients with cancers that have spread only to the pelvic
lymph nodes. Combining orchiectomy with antiandrogen drug therapy
adds a modest benefit. It is an extreme procedure, however,
and studies do not indicate that it improves survival rates
significantly. The median survival rate after the operation
is about 55% over a 40 month period. An estimated 25% of patients
survive five years or more. Nevertheless, orchiectomy, although
irreversible, may produce fewer adverse effects than hormonal
drugs, and interestingly, patients report significantly higher
quality of life after orchiectomy than patients who opt for
hormonal treatment, particularly total androgen ablation.
Cure is possible
in late stage prostate cancer but rare. Even without cure, however,
striking subjective or objective responses to treatment occur in
Unfortunately, in advanced disease, prostate cancer usually returns
within 18 months. In such cases, so-called testosterone-independent
tumors exist, which are not responsive to antiandrogen therapy.
The reason for this is still unknown. One theory is that after cells
that are sensitive to male hormones have been blocked, cells that
are resistant to androgen are stimulated to grow, and the cancer
returns. Some studies have also identified a genetic mutation that
signals the cancer cells to grow in response to other hormones even
in the absence of androgen.
Researchers are continually searching for drugs to treat relapses
and act against these testosterone-independent tumors. Some studies
indicate that when tumors recur after antiandrogen treatments, they
may actually be sensitive to testosterone. If so, administering
androgens at the point of relapse might suppress tumor growth in
some situations. More research is needed for this interesting finding.
ARE THE SURGICAL TREATMENTS FOR PROSTATE CANCER?
is the surgical removal of the entire prostate gland along with
the seminal vesicles (the vessels that carry semen) and surrounding
tissue. The incision can be made in one of the following regions:
The gland and
other structures are then removed. The operation lasts two to four
hours. Advanced surgical techniques called minilaparotomy and laparoscopy
are being developed for radical prostatectomy. These techniques
use smaller incisions, are less invasive, and may cause fewer complications.
(through the abdomen and under the pubic bone, exposing the
entire surface of the prostate).
the perineum (the skin between the scrotum and the anus).
Nerve-Sparing Techniques. Surgical procedures have been refined
over the years, and many operations for localized low-grade prostate
cancer now spare the nerves that control erection.
techniques can improve quality of life. The ability for sexual intercourse
recovers in about a third of patients at three years and nearly
60% at five years after surgery. (Rates vary depending on certain
factors, such as the patient's age. The younger the better.) In
cases where the tumor is bulky and undifferentiated, nerve-sparing
techniques may not be appropriate.
- A bilateral
nerve-sparing procedure saves the nerves on both sides of the
- A unilateral
procedure saves nerves on only one side.
Convalescence. Patients remain hospitalized for up to two
weeks. A temporary catheter used to pass urine is kept in place
when the patient is sent home and usually removed about three weeks
after the operation. The convalescent period at home is about a
month. In general, younger patients with early-stage cancers recover
fastest and experience the fewest side effects.
from Radical Prostatectomy
rates vary after radical prostatectomy and usually depend on the
age of the patient and the experience of the surgeon and medical
center. In one center they have ranged from 4% in men in their 40s
to 14% in men over 70. Complication rates are 10 times higher in
patients who have prostatectomy because of cancer recurrence after
Complications include the usual risks of any surgery, such as blood
clots, heart problems, infection, and bleeding. Complications specific
to radical prostatectomy, incontinence, impotence, and contracture
of the bladder neck, are discussed below. The mortality rate is
very low, about 0.4%.
It should be noted that quality of life usually improves shortly
after surgery, and recovery from certain complications, such as
incontinence and sexual function, can continue to occur even over
Urinary Incontinence. Urinary incontinence is a common complication
and a more distressing side effect of surgery for most men than
sexual dysfunction. When the urinary catheter is first removed following
surgery, nearly all patients lack control of urinary function and
will leak urine for at least a few days and sometimes for months.
Major medical centers report that continence returns within about
18 months for nearly all men under 70 years old and in the great
majority of men older than 70. The average time for return of continence
in one center was just 1.5 months.
A number of approaches may help prevent or treat incontinence.
The first nationally-representative study to evaluate long term
outcomes after radical prostatectomy concluded that impotence occurs
far more frequently than previously reported. The study included
more African American, Hispanic, and young men than previously studied,
although there was little difference among ethnic groups. About
40% of the study subjects considered sexual function a moderate
to big problem, but over 70% still said they would have the surgery
techniques can help prevent incontinence, although even in experienced
centers, 8% of patients will have some postoperative incontinence,
and this rate is much higher (up to 50%) in many community medical
- A procedure
called endopelvic anterior urethral stitch (EAUS) used with
prostatectomy appears to reduce urinary incontinence. In one
small study, 75% of selected patients recovered continence in
a month. The procedure requires a simple stitch at the front
of the urethra.
exercises, contracting and relaxing the muscles used to shut
off the urinary stream, strengthen the muscles on the pelvic
floor and are reported to be very beneficial for many men.
- If incontinence
persists beyond a year, patients may require drug therapy or
surgery. Collagen injections into the urethra, bladder neck
suspension surgery, or a urinary sphincter implant may be helpful
for men who have chronic incontinence. (In one study men had
better results with the sphincter implant.) [ For more information,
Nerve-sparing procedures are also helpful in reducing impotence
as well as incontinence. [See Table Impotence
Rates by Procedure].
Rates by Procedure
Bilateral nerve-sparing procedure
Unilateral nerve-sparing procedure
Non-nerve sparing procedure
Researchers are experimenting with a technique that involves harvesting
nerve tissue from the patient's calf and grafting it into the pelvis
during radical prostatectomy in order to maintain erectile function.
It is still too early to determine whether this procedure will be
effective, and some experts believe it is unlikely to improve sexual
A number of treatments for sexual dysfunction are available that
may help some men. Sildenafil (Viagra), for example, may help restore
potency in an average of 30% of patients. In one study it had an
80% success rate in younger men who were potent before surgery and
had bilateral nerve sparing procedures. (The rate was 40% with only
unilateral procedure.) It may take nine months or longer to respond
to the drug, so men might benefit from alprostadil injections starting
right after surgery to preserve elasticity and help prevent scarring.
It is unlikely to be effective for men over 55 who had unilateral
or no nerve sparing procedures. [
Even when erectile function is preserved, men may experience other
of the Bladder Neck. Another common post-surgical complication
is contracture of the bladder neck at the point where it has been
stitched to the remainder of the urethra. Contracture usually occurs
within the first three months after the operation, causing a sharp
decrease in urinary stream. The condition can be treated by dilation
or surgery on the bladder neck, and rarely recurs.
may not be as rigid as before the operation.
and sexual sensation may be altered.
who retain potency may suffer from retrograde ejaculation, also
known as dry ejaculation. During ejaculation, semen travels
backward into the bladder, causing infertility.
Incontinence. Radical prostatectomy can also cause fecal
incontinence. The risk may actually be higher in men undergoing
is the surgical removal of the pelvic lymph nodes. It is usually
performed at the same time as prostatectomy [ see above ].
If the surgeon suspects that cancer has spread beyond the prostate,
he will perform the lymphadenectomy as part of the operation. Some
surgeons do this procedure as a matter of course when performing
prostatectomy, since it has few complications and adds information
on the state of the disease. The lymph nodes are removed through
an incision in the lower part of the abdomen, using conventional
surgery or laparoscopy, a less invasive variation. The nodes are
immediately examined. If they show signs of cancer, then metastasis
has occurred. In such cases, the operation is usually stopped and
the patient is offered radiation or hormone treatments. Experts
argue about whether a prostatectomy may still be beneficial. One
study found a survival advantage in those who had their prostate
removed even when cancer had spread. More research is needed.
an alternative to standard prostatectomy. And, a 2001 study reported
that it was as effective as radiation therapy (and perhaps more
effective than brachytherapy in patients at medium to high risk.)
Survival in the study exceeded 70%, comparable to radiation therapy
and brachytherapy. Among patients with localized prostate cancer,
the five-year disease-free rate approached 80%. The cryosurgical
technologies used in the study were not as good as newer ones now
available, so these figures even may understate the technique's
The Procedure. The goal of cryosurgery is destruction of
the entire prostate gland and possibly surrounding tissue. Steel
probes are inserted through the skin between the anus and the rectum
and into the prostate. Liquid nitrogen is pumped through the probes
to freeze all prostate cells, both healthy and cancerous. For success,
cryosurgery requires a uniformly frozen area. The dead cells are
absorbed and eliminated by the body. Patients can leave the hospital
in two or three days.
Candidates. Cryosurgery may be considered for patients with
of treatment failure include:
stage local cancer.
that has recurred after radiation treatments.
primary tumors that the surgeon wishes to reduce.
useful for tumors that have spread beyond the prostate if they
have not yet reached the lymph nodes.
- A history
of both hormonal and radiation treatments.
grades 8 and above.
- PSA levels
of more than 10 ng/mL.
Complications are similar to those of standard prostatectomy,
but incontinence rates are much lower. In one study, 85% of
men who were potent before the procedure reported impotence
afterward. Nevertheless 96% reported that they were satisfied
with the results. Incontinence and other side effects may be
higher in patients who have had previous radiation treatments.
Other significant complications include scarring and narrowing
of the urethra and fistulas (abnormal passages from internal
organs to the skin or between two internal organs).
surgical removal of the testicles. It is the single most effective
method of reducing androgen hormones, but it is considered an extreme
procedure. The operation can be done on an outpatient basis, through
a tiny incision in the scrotum, and is relatively pain-free.
Sexual Effects. Many men can still achieve erection after
orchiectomy, but there is almost always a decline in sexual drive.
Men who cannot achieve erection can receive a penile implant. Patients
do not experience a reversal of sex characteristics: the voice does
not change and body hair is not affected.
Quality of Life. Interestingly, patients who choose this
option report significantly higher quality of life afterward than
those who opt for hormonal treatment, particularly total androgen
ablation. Although the operation impairs sexuality, it causes less
fatigue, physical dysfunction, and psychological distress than other
treatments for advanced cancer, excluding no treatment at all. These
studies, however, did not compare orchiectomy to intermittent hormonal
therapy, which may prove to have psychological benefits.
Osteoporosis. Like all androgen deprivation therapies, orchiectomy
increases the risk for osteoporosis, a loss of bone density that
increases the risk for fracture. In fact, the risk for osteoporosis
may be higher with surgery than hormonal drugs.
Enucleation, Holmium laser enucleation of the prostate (HoLEP) is
an investigative procedure that may prove to be preferable to open
ARE THE RADIATION TREATMENTS FOR PROSTATE CANCER?
Two major radiation
treatments are now available:
Advances in both
treatments have been generally equivalent in success rates. In some
cases, both techniques may be used in high-risk patients.
radiation therapy, a physician focuses a beam of radiation directly
on the tumor for 35 three-minute treatments, five times a week,
over seven weeks. 3D conformal techniques use computers and a 3-D
image of the prostate to provide precise targeting of the tumor
using high-dose radiation beams. It allows high doses and poses
a lower risk for inflammation. In a 1998 study, the higher-dose
conformal therapy significantly improved survival rates compared
to lower dose treatment. Men who have had transurethral resection
of the prostate (TURP) or have a history of lower urinary tract
symptoms may have a better experience with external-beam radiation
using 3D conformal techniques.
is an outpatient technique that implants radioactive "seeds" directly
into the prostate. Implants can be temporary or permanent. Temporary
implants are usually accompanied by external-beam radiation. This
procedure requires more skill than external-beam radiation therapy,
and even with experienced physicians, the distribution of radioactive
seeds is uneven in 15% of cases, increasing the risk for insufficient
Computerized systems are being developed to help oncologists optimize
seed placement and allow precise treatment for each patient and
higher radiation doses. Eventually, it could improve tumor control,
reduce side effects, and cut costs.
It should be noted, that it is common for PSA levels to temporarily
rise, or "bounce," following seed implantation without it being
a signal for cancer recurrence. This effect can produce anxiety
and can interfere with the diagnosis of true recurrence.
Candidates. Studies are indicating the brachytherapy is useful
for select patients, specifically those with prostate volumes less
than 60 mL and who have early-stage prostate cancer (T1 or T2 tumors,
a Gleason grade lower than 7, and PSA levels below 10 ng/mL). It
may be beneficial in patients with inflammatory bowel disease or
with cancer close to the bowel. Poor candidates for brachytherapy
include men who have had TURP and patients with advanced cancer,
high-grade tumors, or very enlarged prostate glands.
The side effects
of radiation therapy include most of those of surgery, but the risks
for impotence and incontinence are considerably lower. A 2000 study
concluded that adjuvant radiation therapy (given right after surgery)
in moderate doses does not increase the risk for long-term urinary
incontinence or sexual dysfunction beyond that of surgery alone.
Gastrointestinal Complications. Complications in the gastrointestinal
are common. Short-term effects include:
The risk for incontinence is about 7% to 20%. Patients treated
with radiation may experience a painful, but usually temporary,
urinary tract inflammation. About 10% to 15% of patients develop
a long-term urgent and frequent need to void their bladder. Brachytherapy
carries a lower risk for urinary incontinence.
- Loss of
is a very common side effect and can last for the duration of
therapy. It is usually treated with Lomotil. A few patients
have diarrhea flare-ups for years afterwards. Less than 1% suffer
more serious intestinal problems.
is potential for injury to the rectum with brachytherapy. Ulcers
in the rectum occur in over 10% of patients, but the risk decreases
with greater experience in the technique.
Scarring and narrowing of the urinary tract (stricture) may occur,
particularly in men who had TURP performed within a short time before
radiation treatment. In such men, radiation treatments should be
delayed by four to six weeks. If the prostate has been injured or
damaged or the bladder is easily irritated, side effects with brachytherapy
may actually be worse than with other procedures.
Impotence. Risks for impotence are around 40% in men who
have brachytherapy and are between 60% and 70% or higher with external
beam radiation. Although brachytherapy may pose less of a risk for
impotence than external-beam radiation or surgery, one study reported
a high long-term rate of impotence (53%) after five years. Sildenafil
(Viagra) may be effective for 70% of men experiencing impotence
following radiation therapy for local prostate cancer. Other treatments
may also be useful. [ See also Report #15,
Impotence.] A 2000 study suggested that the dose of radiation
received by the bulb of the penis correlates with risk of impotence.
If this is confirmed by further study, carefully designed radiation
may improve current rates.
Radiation or Other Nonsurgical Procedures
Radiation Treatments. Investigators are also testing radiation
treatments that use a combination of neutrons and protons (mixed-beam)
or proton beams rather than the standard proton radiation therapy.
High-Intensity Focused Ultrasound (HIFU.). Studies are reporting
promise with an intensive ultrasound procedure called transrectal
high-intensity focused ultrasound (HIFU). It allows for very precise
minimally-invasive removal of tissue in local prostate cancers.
It may eventually prove to be an alternative to radiation therapy.
More research, with long-term follow up, is needed.
Thermoradiotherapy. Thermoradiotherapy is a procedure that
combines heat and conformal radiation. A 2000 study reported that
it is a well-tolerated treatment for prostate cancer. The researchers
reported a significant drop in PSA, but more research is needed.
Implanted Magnetic Rods An interesting and unique procedure
implants very small rods that heat up when exposed to a magnetic
field and destroy surrounding tissue. The rods are permanent, so
therapy can be repeated non-invasively if the patient's PSA levels
rise. The US Food and Drug Administration has approved a clinical
study at the University of California San Francisco, treating patients
who have recurring cancer after undergoing radiation therapy.
ARE THE HORMONAL DRUG TREATMENTS FOR PROSTATE CANCER?
Suppression Drug Therapy Guidelines
either drugs or orchiectomy (surgical removal of the testicles),
is used under the following circumstances:
is irreversible, about 75% of patients with advanced prostate cancer
choose drug therapy to block androgens. It should be noted that
hormonal therapy is not a cure. Further, between 20% and 30% of
patients do not respond to hormonal treatment; success rates given
in studies then are not based on the total cancer patient population.
therapy is used if treatment for localized prostate cancer has
failed and cancer recurs (as indicated by rising PSA levels).
therapy is used for treating advanced or metastasized prostate
The primary agents
used for suppressing androgens are called luteinizing hormone-releasing
hormones (LH-RH) agonists. They include:
block the pituitary gland from producing hormones that stimulate
testosterone production. Patients must have injections of LH-RH
agonists for the rest of their lives.
(Lupron, Leuprogel). Studies report that disease progression
is prevented in 72% of men taking daily leuprolide and up to
89% of those taking monthly injections. Certain men, however,
may not respond to injections. Drug delivery using implants
is under investigation.
(Zoladex). Partial responses of 60% to 80% have been reported.
Testosterone and PSA Surges. Treatment with LH-RH agonists
produces a testosterone surge in the first week, which may actually
intensify symptoms. After this phase, testosterone levels drop to
near zero. Leuprogel, a newer leuprolide, may pose a lower risk
for this effect. Researchers are investigating other drugs, such
as GnRH antagonists, that do not produce this surge. [ See below.
LH-RH agonists can also cause PSA levels to rise temporarily. A
2000 study suggested that administering flutamide, a drug known
as an antiandrogen, for two weeks prior to LH-RH agonists may not
only prevent PSA surge but also induce early declines in PSA levels.
Side Effects. Side effects include hot flashes and occasionally
nipple and breast tenderness.
are powerful agents produced in the adrenal gland. They are used
alone or in maximal androgen blockage (MAB), in which they are combined
with LH-RH agonists or orchiectomy to completely block androgen
hormones. Antiandrogens are either steroidal or nonsteroidal.
Nonsteroidal Antiandrogens. The nonsteroidal drugs are as
Antiandrogens. The steroidal antiandrogens act like female hormones
and include the following:
(Eulexin, Drogenil). Flutamide has produced extended response
in some patients. Interestingly, studies report that simple
withdrawal produced a PSA decrease in about 20% of patients,
which lasted between 3.5 and 5 months. Side effects reported
with flutamide include diarrhea and liver damage, which has
been fatal in rare cases; liver function must be monitored closely.
(Nilandron). Nilutamide is associated with reversible interstitial
pneumonitis, nausea, alcohol intolerance, and visual disturbances.
(Casodex). Bicalutamide may be as effective and have fewer severe
side effects, including loss of sexual interest and osteoporosis,
than other antiandrogens. This agent is proving to be an alternative
to maximal androgen blockage (MAB) using goserelin plus flutamide
or orchiectomy. In a comparison study with MAB, survival rates
were similar. The bicalutamide group reported more breast swelling
but the MAB group had significantly worse diarrhea and hot flashes.
Both groups reported impaired sexual function. Physical capacity
increased in those taking bicalutamide and decreased in the
MAB group. In a comparison study with orchiectomy, patients
taking bicalutamide had more sexual interest and physical capacity,
and preliminary data indicates that bicalutamide does not deplete
bone mineral density.
Acetate. (Megestrol acetate suppresses androgen production,
but incompletely, and is generally not used as initial therapy.)
acetate. (Cyproterone combined with estrogen may prevent the
testosterone surge that occurs with LH-RH agonists.)
Releasing Hormone (GnRH) Antagonists
releasing hormone (GnRH) antagonists are relatively recent agents.
Those studied include abarelix and histrelin. (GnRH is another name
for luteinizing hormone-releasing hormones (LH-RH). Drugs known
as GnRH antagonists have two advantages over LH-RH agonists:
In one study,
histrelin was administered as an implant and was effective for up
to 30 months. This offers an advantage over existing drugs, which
must be administered at one to three -month intervals.
- They do
not cause the same testosterone surge that can temporarily worsen
- They seem
to reduce testosterone levels more quickly.
diethylstilbestrol (DES), may also be used. These female hormones
may exacerbate heart conditions in high doses and their use has
declined. Other estrogens, such as fosfestrole, may prove to be
effective without posing such high risks. An estrogen agent, estramustine
phosphate, which is also used in chemotherapy, is showing promise.
Treatments for Maximal Androgen Blockage (MAB)
even after using standard hormonal agents, residual testosterone
is usually present. In such cases, physicians may try drugs or techniques
to produce a complete shut-down of all male hormones. This approach,
known as maximal androgen blockage (MAB), uses LH-RH agonists or
orchiectomy combined with other agents known as antiandrogens. MAB,
however, has considerable adverse effects on quality of life, and
studies suggest that survival benefits are very modest over androgen
suppression with single agents or orchiectomy. (One 2000 study suggested
that taking MAB longer than 120 days may improve survival times.)
Intermittent Androgen Suppression. Oddly, stopping
antiandrogens sometimes causes PSA levels to drop again, a phenomenon
called the antiandrogen withdrawal syndrome. This has led to investigation
of therapy that uses intermittent androgen suppression, which involves
alternating cycles of therapy and rest. First, antiandrogen drugs
are given for at least six months until PSA levels are at their
lowest and remain there. The drugs are then stopped until PSA levels
rise again to greater than 10 ng/ml, at which point treatment resumes.
This cyclic therapy appears to delay tumor progression, and in any
case, it offers a drug-free period in which the patients experience
renewed sexual function and a greater sense of well-being.
Sequential Androgen Blockage. Sequential androgen blockage,
like intermittent androgen suppression, is designed to effectively
reduce the effects of testosterone while offering the patient some
relief from side effects. It uses drugs known as 5 alpha-reductase
inhibitors to block conversion of testosterone to dihydrotestosterone
along with an antiandrogen to mop up any residual male hormones.
This treatment allows some testosterone to remain in circulation
and helps prevent some of the distressing side effects of total
of Androgen Deprivation
Men often experience
fatigue, loss of energy, and emotional distress. Hormonal therapy
may significantly impair quality of life, particularly in men who
had no symptoms beforehand and whose cancer has not metastasized.
Common side effects of androgen suppression drugs include the following:
Needless to say,
these side effects can cause severe emotional problems.
the loss of bone density. This risk is higher with orchiectomy
than with androgen suppressants. It does not occur with all
androgen suppressants. The use of estrogens may actually be
- Loss of
- Loss of
sexual drive and sexual dysfunction
of the breasts (gynecomastia)
- Hair loss
Therapies for Manipulating Hormones
cancers after androgen suppression fails, researchers are investigating
the use of other therapies that affect hormonal triggers of prostate
Ketoconazole. Ketoconazole, usually used to fight fungal
infections, is a nonhormonal drug that inhibits an enzyme that stimulates
production of testosterone. It is effective in high doses but can
have severe gastrointestinal effects, mainly nausea and anorexia.
Long term use can result in impotence, itchy skin, nail changes,
and suppression of stress hormones. One center reported a consistent
PSA response in more than 60% of patients who had failed other androgen
Aromatase Blockers. Drugs, such as aminoglutethimide (Cytadren)
that block aromatase, an enzyme important in estrogen production,
are being studied. Because the female hormone estrogen plays such
a major role in the development of breast cancer, some experts postulate
that blocking the small amount of estrogen found in men may also
affect prostate cancer. Side effects include drowsiness and skin
ARE NONHORMONAL DRUGS USED FOR PROSTATE CANCER?
for prostate cancer improves symptoms but standard agents have not
improved survival rates. A number of drugs are being investigated,
both alone and in combinations, for cancer that is unresponsive
to hormone treatments. These drugs include vinblastine, mitoxantrone,
vinorelbine, adriamycin, mitoxantrone, and estramustine (which combines
estrogen with nitrogen mustard and acts on prostate cells). Amsacrine
and etoposide, which break down DNA, may prove to be effective for
men with certain inherited forms of prostate cancer. Unfortunately,
studies to date are reporting toxicities and lack of effect with
some of these agents. A study of vinorelbine had more encouraging
results; the drug was shown to be safe and provided relief from
symptoms, especially bone pain. Paclitaxel and docetaxel, drugs
used in gynecologic cancers, are also showing promise.
such as prednisone, are important for reducing pain and improving
quality of life. Some experts believe they should be the first choice
for progressive prostate cancer that is resistant to hormonal treatments.
Corticosteroids may be particularly effective in relieving pain
and delay disease progression when used in combination with chemotherapy
drugs, particularly mitoxantrone. There is evidence that corticosteroids
can reduce PSA levels and boost survival in some patients.
for cancer uses agents that enhance the power of the patient's own
immune system to fight cancer cells.
Vaccines. One technique employs genetically-designed vaccines
that inject factors into prostate cancer cells to serve as antigens
so that the immune system is tricked into attacking the real cancer
cells. A number of vaccines (eg, Provenge, Gvaz, JBT 1001) are in
clinical trials. Researchers have identified an antigen that may
be unique to prostate cancer cells and so a potential very effective
target for a vaccine.
Monoclonal Antibodies. Monoclonal antibodies are genetically
designed immune factors that target and attack specific antigens
and are being tested with prostate cancer cells.
are proving to be very helpful for reducing bone pain in metastasized
cancers. These drugs actually help inhibit prostate cancer cell
growth in the bone.
A number of non-hormonal
drugs are under investigation.
Potent Nonsteroidal Anti-inflammatory Drugs. COX-2 inhibitors
and potent NSAIDs, such as exisulind or sulindac (Clinoril), are
being investigated for treating and delaying recurrence of prostate
cancer after surgery.
Vitamin-D Derived Treatments. Some studies are reporting
that vitamin-D derived agents, such as calcitriol, may eventually
be beneficial for prostate cancer patients, particularly in combination
with other chemotherapies. Liarozole blocks the break down of retinoid
acid (a vitamin A derivative important in maintaining normal cell
growth and structure) and is showing promise for reducing PSA levels
and improving symptoms in early trials.
Angiogenesis Inhibitors. Thalidomide, and AE-941 (Neovastat)
are investigative agents that inhibit angiogenesis, the formation
of new blood vessels that are critical for spreading cancer. It
is still too early to determine whether these therapies will be
Matrix Metalloproteinase Inhibitors. Drugs are being tested
in clinical trials that inhibit matrix metalloproteinase, which
are enzymes that may degrade cell structure allowing cancers to
grow and metastasize.
Doxazosin. Doxazosin (Cardura), a drug commonly used to treat
benign prostatic hyperplasia, has been shown to kill prostate cancer
cells in lab experiments. The effects are amplified when doxazosin
is combined with adriamycin or etoposide, chemotherapy drugs. More
research is needed to determine if this effect has significance
PC-SPES. An extract from eight Chinese herbs referred to
as PC-SPES is showing promise in reducing PSA levels by up to 80%
in some men. Side effects include breast swelling, leg cramps, nausea
and vomiting, and blood clots due to the estrogenic activity of
Quercetin. Q uercetin is a flavonoid compound found in apples,
onions, black and green tea, red wine, green leafy vegetables, beans,
and citrus fruits. It may have specific actions that block androgen
activity in prostate cancer cells, making it a good research subject.
Atrasentan. Atrasentan shows promise in reducing bone loss
and delaying progression of prostate cancer in men with advanced
disease that no longer responds to hormone therapy. Side effects
are relatively mild.
ELSE CAN HELP BE OBTAINED FOR PROSTATE CANCER?
National Cancer Institute Call (800-4-CANCER) (800-422-6237) during
working hours. Deaf and hard of hearing callers with TTY equipment
may call (800-332-8615) Call CancerFax at 800-624-2511 or 301-402-5874
from your touch-tone phone or from the telephone on a fax machine
(the machine must be set to touch-tone dialing). or on the Internet
American Cancer Society, 1599 Clifton Road, NE, Atlanta, GA 30329-4251
Call (800-ACS-2345) or (404-320-3333) or on the Internet (http://www.cancer.org)
American Society of Clinical Oncology, 1900 Duke Street, Suite 200,
Alexandria, VA 22314 Call (703) 299-0150 or on the Internet (http://www.asco.org)
National Prostate Cancer Coalition, 1156 15th St., NW, Washington,
DC 20005. Call (888-245-9455) or on the Internet (http://www.4npcc.org)
Cancer Care, Inc., 275 7th Avenue, New York, NY 10001, Call (800-813-HOPE)
or (212-712-8080)or on the Internet (http://www.cancercare.org/index.asp)
American Foundation for Urologic Disease , 1128 North Charles Street,
Baltimore, MD 21201. Call (800-242-2383) or (410 468-1800)or on
the Internet (http://www.afud.org/)
Digital Urology Journal 300 Longwood Avenue, Hunnewell 3, Boston,
An online journal with research articles on urologic problems is
located at (http://www.duj.com/)
National Association for Continence (NAFC), Box 8310, Spartanburg,
SC 29305-8310 Call (800-BLADDER) or on the Internet (http://www.nafc.org/)
Offers free literature. Paid membership includes a resource guide,
a quarterly newsletter, the Resource Guide (a very comprehensive
directory of products and services for the incontinent), and referrals
to physicians who specialize in continence. Acts as an advocate
for the incontinent with governmental agencies, insurance companies,
and health organizations.
The Simon Foundation for Continence, Box 835-F, Wilmette, IL 60091
Call (800-23-SIMON)or on the Internet (http://www.simonfoundation.org)
American Institute for Cancer Research (AICR), 1759 R Street N.W.,
Washington, D.C. 20009. Call 1-800-843-8114 or (202) 328-7744 in
Washington, D.C. Internet source for dietary recommendations: (http://www.aicr.org)
For Internet Users
Listing of clinical trials (http://www.centerwatch.com/studies/listing.htm)
Journal of Clinical Oncology (http://www.jco.org/)
National Comprehensive Cancer Network (http://www.nccn.org/)
PSA Rising Magazine (http://www.psa-rising.com/)
Useful site for learning about cryosurgery (http://members.aol.com/dtkn21/endo/tcap_info.html)