You have described every prostate cancer patient's (and their doctor's)
worst nightmare.  I am sure when your oncologist saw the Gleason 10 and the
mets throughout, his only concern was knocking it down ASAP.  If there are
mets throughout his skeletal structure, you can bet there are bets in soft
tissue.  When it gets into (and grows within) the liver or brain, it's
lights out.  So, your doc went after it with the best one-two punch known to
current medicine: Casodex and Lupron.

Frankly, if he had not been successful, your husband would not have had
enough time left to worry about paralysis.

However, he was successful in knocking it down to 0.6.  He can now start
looking at other issues and treatments, all of which, I am sorry to say, are
palliative.

Some of the larger mets that are not surrounded by sensitive and vital
organs might be radiated to kill off the cancer, especially if they are
causing pain.  But, keep in mind, radiation kills cells indiscriminantly
and, therefore, comes with its own baggage.  Surgery to reduce masses are
not unheard of.

Also, the onc may prescribe a medication such as Fosamax in order to help
the damaged bone regenerate.  At least one study showed that this also
helped fight the cancer.  Side effects may include nausea.  Other side
effects are long term.

Absolutely!  Your husband, if he is like most of this, is missing most of
the cognitive input on this.  The stunning that cancer diagnoses does to men
prevents him from functioning thoughtfully for some time.  While I thought I
was fully functional, I now know that I was 80% at best for almost a year.
Some literally require someone else to research the disease and make
decisions for them.

You need also read up on it so that you can search intelligently for
studies.  There is so much going on in prostate cancer research now (on both
sides of the pond) that you should have no problem finding one or two or
more for which your husband would qualify.  Obviously, no one has been cured
yet in these, but some have had their lives extended and/or pain reduced.

Thanks, Dora, but right now I am almost euphoric with my stats.  I just may
live another ten years.

Advanced prostate cancer
Endocrine therapies and palliative measures

This article reviews the key points in managing metastatic prostate
cancer, including risk-benefit considerations of systemic treatment. The
authors point out that the primary care physician not only provides
direct care, but also serves as a sounding board and acts as an
intermediary between the urologist and the patient.

Metastatic, or advanced, prostate cancer is a clinical entity distinct
from other forms of cancer in a number of ways.

1. The urologist is usually the key treating physician for patients with
advanced prostate cancer. With most types of metastatic cancer in the
United States, the oncologist is the primary treating physician. But
with prostate cancer, it is the urologist who not only makes the initial
diagnosis and institutes local therapy, but also usually first detects
the presence of metastatic disease and informs the patient and family.
In addition, the urologist often initiates systemic therapy, almost
always with endocrine, or hormone, therapy. When metastatic disease is
refractory to hormone therapy, some patients are referred to an
oncologist, but even in that situation, the urologist may continue to
provide follow-up care.

Having the urologist as the treating physician for patients with
metastatic disease offers the advantage of continuity of care, because a
long-standing clinical relationship is often in place when advanced
disease is detected. This is particularly important when a patient has
prostate cancer, a situation in which difficult quality-of-life issues
demand that decisions be made on an individual basis. Specifically, the
degree of proactivity in therapy is a common and challenging issue in
treatment of metastatic prostate cancer, and a close, long-term working
relationship with the patient and family is extremely helpful in
decision making.

2. The relatively slow progression of metastatic prostate cancer and the
advanced age of many patients are key factors in decision making.
Advanced prostate cancer can be a devastating clinical condition, but
the natural progression differs from that of most solid tumors. Before
the advent of testing for levels of serum prostate-specific antigen
(PSA), when metastatic disease was diagnosed by positive bone scans and
symptoms such as bone pain, the 5-year relative survival rate for
patients was 28%; this rate is far greater than that seen with other
common cancers that have metastasized (table 1). In the 1990s,
metastatic prostate cancer is usually diagnosed much earlier because of
serial PSA monitoring, so survival, and hence the period of treatment,
is even more prolonged.

Table 1. Five-year relative survival rates for patients with common
cancers (1983-1987)  Prostate 28%
Lung 1.3%
Colon 6%
Pancreas 1.4%
Breast (female) 17.8%
Adapted from Miller BA et al, eds. Cancer statistics review. Bethesda:
National Cancer Institute, 1992. US Department of Health and Human
Services, NIH publication No. 92-2789.

The tumor biology of this condition, then, must be factored into the
patient's overall clinical status to determine a treatment plan. Elderly
patients and those with significant comorbid disease may be treated more
conservatively than patients who have a longer life expectancy.

3. Endocrine therapy is the first and primary means of systemic
treatment of patients with metastatic prostate cancer. Other than breast
cancer, prostate cancer is the only common cancer in which endocrine
therapy is a mainstay of treatment. Standard initial treatment of
patients with metastases is with some form of this "kinder, gentler"
therapy, often for prolonged periods. The strategy is beneficial in most
patients, and the minimal side effects mean that patients receiving
endocrine therapy often can live more comfortably than do many patients
who are receiving chemotherapy.
The major differences between the treatment options are side effects and
cost. Because the urologist is usually the treating physician, the
primary care physician is likely to be in the role of either advising
the patient about the preferred choice of therapy or assisting in
management of side effects.

The remainder of this article reviews key points in the management of
metastatic prostate cancer, including the rationale for and risk-benefit
considerations of systemic treatment, common side effects of hormone
therapies, and methods of palliation.

Endocrine therapy

More than 50 years ago, the critical relationship was identified between
serum testosterone levels and the growth of prostatic tissue. Clinically
useful remissions of metastatic prostate cancer were achieved after
bilateral orchiectomy and by oral administration of estrogens. These
treatments have now been superseded by newer endocrine therapies that
have similar pathophysiologic rationales but less treatmentinduced
morbidity.

The key physiologic pathways of endocrine therapy are depicted in figure
1. About 95% of total serum testosterone is produced by the testes. The
remaining 5% is accounted for by secretion of adrenal androgens that are
converted to testosterone. Both testicular activity and adrenal activity
are controlled by the hypothalamus and the anterior pituitary gland.
Circulating testosterone is bound in plasma by proteins, and the small
unbound fraction passively diffuses into prostate cells, where it is
converted by the enzyme 5-alpha-reductase to dihydrotestosterone, which
in turn is bound in the cytoplasm and transported to the nucleus, where
stimulation of cell division occurs.

The main forms of endocrine therapy for prostate cancer interfere in
some manner with this basic pathway of androgen stimulation of prostate
cancer cells. About 75% of patients with metastatic prostate cancer
experience tumor response to the initial form of endocrine therapy.
Bilateral orchiectomy--This form of endocrine therapy is the standard by
which the effectiveness of other treatments is judged. The advantages
are a relatively low cost, lack of a need for long-term patient
compliance with a regimen, and the immediacy of change in the patient's
hormonal milieu. The chief disadvantage relates to an alteration in body
image.

It is important to clarify for the patient exactly what the procedure
entails and to stress that the scrotum and penis are left intact. The
term "castration" should be avoided. The surgical procedure itself has a
minimal risk of complications. As with other forms of androgen ablation
therapy, the major side effects are loss of libido, impotence, and hot
flashes. Testicular prostheses can help to reduce psychological
morbidity, but due to patient preferences, they are generally not used.

Although bilateral orchiectomy has been replaced by use of luteinizing
hormone-releasing hormone (LHRH) agonists as usual first-line endocrine
therapy for metastatic prostate cancer, it continues to be a viable
option for patients who are not emotionally troubled by this approach.
This therapy is particularly favorable for patients who do not have
ready access to medical care or cannot afford the cost of medications
required in other forms of endocrine therapy.
Estrogens--The second "classic" form of endocrine therapy is
administration of oral estrogen preparations. Although there is some
controversy about the main mechanism of action of estrogens, it is
generally accepted that the key is negative feedback on the
hypothalamus.

This leads to decreased secretion of
LHRH, which lowers gonadotropin secretion from the pituitary. The result
is inhibition of testicular Leydig cell production of androgens. After
about 2 weeks, postorchiectomy levels of serum testosterone are
achieved.
It has also been postulated that estrogens have a direct cytostatic
effect on prostate cancer cells and that high-dose intravenous
phosphorylated stilbestrol can lead to immediate relief of symptoms of
metastases, perhaps through a poorly defined direct effect on tumor cell
deposits. Estrogens also directly inhibit testicular metabolism and
increase the level of testosterone sex-binding globulin, which lowers
the free serum level of the hormone.

The usual oral preparation of estrogen for use in prostate cancer is
diethylstilbestrol (DES), which is administered in a daily dose of 1 to
3 mg. Estrogen therapy does not carry the psychological morbidity of
orchiectomy, but it is associated with potentially significant side
effects.
In addition to the usual side effects of androgen suppression, the most
significant negative consequence of this therapy is an increase in risk
of cardiovascular events (including myocardial infarction),
cerebrovascular events, and pulmonary emboli.

Another side effect is gynecomastia, which may cause pain, but this
complication can be avoided with pretreatment low-dose radiation therapy
to the breasts for 3 days. Although estrogen therapy is not costly, it
is seldom used as first-line treatment because of side effects.

LHRH agonist therapy--Use of LHRH agonists has become the most common
endocrine therapy for prostate cancer. These agents act initially at the
level of the pituitary to stimulate LH release, resulting in a transient
surge in serum testosterone levels. This causes feedback to the
hypothalamus to deplete LH levels, resulting in the medical equivalent
of orchiectomy. However, these agents do not affect adrenal production
of androgens.

Naturally occurring LHRH is a decapeptide with a short half-life. Far
more potent are the synthetic agonist preparations, including goserelin
acetate (Zoladex) and leuprolide acetate (Lupron). In their long-acting,
parenteral formulations, these agents are to be administered every 3
months. Goserelin pellets are administered by subcutaneous injection,
usually into the abdominal wall through a wide-bore needle (14- to
16-gauge). Discomfort at the injection site can be decreased by
administration of a local anesthetic. Leuprolide has usually been given
intramuscularly with a conventional needle on a monthly basis. A 3-month
depot injection is now available for both goserelin and leuprolide.

The main side effect associated with LHRH agonist therapy is the
so-called flare reaction, in which tumor-related symptoms transiently
worsen during initial treatment. Associated with a testosterone surge,
the flare reaction may include an increase in bone pain. One preventive
strategy is to pretreat patients with a 2-week course of an antiandrogen
(bicalutamide [Casodex] or flutamide [Eulexin]). This approach is most
often considered for patients with bone metastases.

Pituitary desensitization and castrate levels of androgens occur after
about 5 days of LHRH administration. As with other hormone therapies,
hot flashes, loss of libido, and impotence may occur.
The link between long-term LHRH suppression of testosterone production
and effective antitumor activity has been clearly demonstrated.
Randomized trials have shown treatment benefits to be equivalent to
those of orchiectomy and estrogen administration.

As already noted, androgen suppression is effective therapy in about 75%
of patients with metastatic prostate cancer. But in virtually all
patients, resistance to treatment eventually develops. The average time
from initiation of therapy to disease progression varies from 18 to 48
months.

The long-term costs of LHRH agonist therapy are greater than those of
orchiectomy, but most patients with metastatic prostate cancer are
elderly and on Medicare, which covers the costs of this therapy.

Antiandrogens--Since testicular suppression of androgen production still
leaves patients with substantial levels of circulating androgens from
the adrenal glands, it has been postulated that a combination of agents
to deal with all sources of androgens could be a more effective
treatment strategy.

The nonsteroidal (pure) antiandrogens, flutamide and bicalutamide, have
been used in combination with androgen suppression to achieve so-called
combined, or total, androgen blockade.

Antiandrogens enter prostate cancer cells and interfere with the
interaction of dihydrotestosterone with androgen receptors. This
strategy appears to result in greater antitumor effect than does LHRH
agonist monotherapy, particularly in patients who are in generally good
medical condition and who have smaller cancers. However, the advantage
of combination therapy over monotherapy is modest, and controversy
continues about the appropriate role for this strategy.
These agents are administered orally. Flutamide must be administered
every 8 hours and is commonly associated with diarrhea; the mechanism
for this side effect, however, is unknown. Breast and nipple tenderness
have also been observed. Bicalutamide has a longer half-life than
flutamide, which allows daily administration, and appears to cause fewer
toxic effects.

Side effects of endocrine therapy
Perhaps the most troubling symptom of any therapy intended to suppress
androgen levels is hot flashes, which may be severe. A variety of
pharmacologic agents have been used to ameliorate this problem,
including the alpha agonist clonidine hydrochloride (Catapres), the
belladonna-phenobarbital-ergotamine tartrate combination Bellergal-S,
megestrol acetate (Megace), and low-dose estrogens.

While erectile dysfunction is commonly seen with therapy for localized
prostate cancer, particularly radical prostatectomy, androgen
suppression also results in an essentially complete loss of libido. The
implications of this side effect obviously are related to the patient's
pretreatment levels of sexual interest and activity.

Elderly patients may find this side effect less troubling than do
younger men, but this is not always the case. It is important to discuss
with the patient that the emotional desire for intimacy and physical
contact is not impaired by androgen suppression and that patients are
able to engage in noncoital sexual experiences.

When the cancer progresses
Patients whose prostate cancer has progressed after first-line endocrine
therapy have many of the same needs and challenges as other patients
whose solid tumors have progressed beyond initial therapy. The mechanism
for "hormone escape" is thought to be clonal selection of
androgen-independent tumor cell lines, and second-line endocrine therapy
is generally futile. The availability of serial PSA monitoring means
that progression of the disease while the patient is undergoing androgen
suppression therapy is usually detected through blood testing, before
progression of symptoms.

For patients whose cancer has progressed after monotherapy with either
LHRH agonists or orchiectomy, it seems logical to consider the addition
of an antiandrogen to counteract adrenal androgens at a tumor cell
level. Unfortunately, this approach is rarely useful. Some reports,
however, have stated that for patients initially treated with combined
androgen suppression and antiandrogen therapy, withdrawal of the
antiandrogen may lead to an antitumor withdrawal response similar to
that seen in breast cancer patients when the antiestrogen tamoxifen
citrate (Nolvadex) is withdrawn.

Another option is estramustine phosphate sodium (Emcyt), a combination
of nitrogen mustard and a phosphorylated estradiol. The antitumor effect
of this therapy is due to its ability to bind to microtubule-associated
proteins. This agent is concentrated preferentially in the prostate and
has been reported to cause subjective and objective improvement in 30%
to 60% of patients. However, as with other chemotherapeutic agents,
toxicity can be considerable, particularly in elderly, frail patients.

Other chemotherapeutic approaches, including use of taxanes, have been
disappointing in their efficacy. In addition, because patients often
require multiple courses of radiation therapy for relief of bone pain,
bone marrow reserve may not allow adequate dosing with cytotoxic agents.

Because a variety of growth factors appear to be important to the
development and progression of prostate cancer, anti-growth factor
strategies have been devised. Suramin is a polysulfonated naphthylurea
agent with a number of biologic effects, including inhibition of growth
factor. This agent has shown promising activity in prostate cancer that
has metastasized to bone, with efficacy greater in patients who are in
good general medical condition and who have lower total-body tumor cell
burdens. Side effects are substantial, however, and include skin rash,
prolonged bleeding time, keratopathy, and neuromuscular toxicity.

Methods of palliation

Bone pain is the most common symptom requiring relief. Some patients
benefit from therapy with biphosphonates, which suppress bone resorption
and mineralization by a direct effect on osteoclasts.

Local radiation therapy to areas of painful, bony metastases relieves
symptoms in most patients. For patients with multiple sites of painful
metastases, wide-field radiation therapy, such as hemibody irradiation,
may improve symptoms but also carries greater risk for side effects,
such as nausea, vomiting, and diarrhea.

Another treatment possibility is strontium-89 chloride, a beta-emitting
isotope with a half-life of 50.5 days. This agent is localized
preferentially in sites of increased bone turnover, including
osteoblastic metastases in prostate cancer. In normal bone, turnover is
about 2 weeks, but metastatic tumor cell deposits retain the agent
almost indefinitely. Strontium-89 chloride has been clearly demonstrated
to provide effective pain relief in a significant proportion of patients
with metastatic prostate cancer. Pain relief typically occurs within 1
to 2 weeks after administration of a single intravenous dose. Side
effects are minimal and consist mainly of bone marrow suppression. This
therapy is ideal for patients with multiple sites of bony metastases
whose white blood cell count is over 3,000/mm3 and platelet count is
above 60,000/mm3. About 90% of this agent is excreted by the kidney, so
dose modifications may be required in patients with renal insufficiency.

Summary

Management of patients with metastatic prostate cancer differs from that
of patients with other metastatic solid tumors. Because the treating
physician is usually the patient's urologist, the primary care
physician's main role may be to relieve pain and treat the patient for
common side effects of hormone therapies. By being familiar with the
forms of systemic treatment-including orchiectomy and the use of
estrogens, luteinizing hormone-releasing hormone agonists, and
antiandrogens-the primary care physician can also assist patients in
making treatment decisions that are individualized to the specifics of
disease state, comorbid conditions, age, and value systems.

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1989:253-60
Dr Taub is in private practice of urology and Dr Begas is in private
practice of oncology in Boca Raton, Florida. Dr Love is associate
clinical professor, department of medicine, division of hematology and
oncology, University of Miami School of Medicine. Mailing address: Neil
Love, MD, 1150 NW 14th St, Suite 509, Miami, FL 33136.point out that the
primary care physician not only provides direct care, but also serves as
a sounding board and acts as an intermediary between the urologist and
the patient.

knowledge is power - growing old is mandatory - growing wise is optional    
"Many more men die with prostate cancer than of it. Growing old is
invariably fatal. Prostate cancer is only sometimes so."
http://community.webtv.net/PALMER_ENT/doc