JLA Mindfulness course 2015 MEDICARE REBATES

May 2004 vol. 7, no. 2 New Developments in Prostate Cancer Treatment
Save
the
Date!
PCRI 2004 Regional Conference Scheduled for October
This yearвЂ™s PCRI regional prostate
cancer conference will be held on
Saturday, October 9 in the Mayer
and Hastings auditoriums on the USC
Norris Campus in Los Angeles. Many of
the events that have made PCRI
conferences so popular will again be staged:
Free PSA testing, CME credit, eminent panels of
speakers and information booths.
вќЏ
Patient and Physician in Co-Partnership
About the Medical
Articles in this Issue
The Linkage Between Obesity and
Prostate Cancer
By David Heber, MD (Page 6)
There is a broad base of evidence that obesity
may promote the development and progression
of prostate cancer. In this article, Dr. Heber first
compares the incidence of cancer within countries where obesity is rare to that of the U.S. and
other Western countries. He then examines the
biological processes that are common to both
obesity and cancer that could lead to a causal
interrelationship. He cites numerous sources
that correlate high fat intake with prostate cancer. He contends that the effects of a high-fat diet
on PC are partially explained by the changes in
hormones resulting from that diet and by the
decreasing body mass associated with aging. He
concludes that for PC and other common forms
of cancer, there is a clear association of obesity
with cancer risk, incidence, or progression.
Options for Post-Prostatectomy
Incontinence
By Gary E. Leach, MD (Page 8)
Dr. Leach defines the main causes of post-prostatectomy incontinence as (1) high pressure developing in the bladder as the bladder fills, (2)
damage to the sphincter muscle, and (3) a combination of the two: With treatment directed by
a process called urodynamic testing that measures urinary flow, he says, the majority of men
are able to experience significant improvement
in urinary control. Medications such as Detrol,
Ditropan, and the Oxytrol patch relax the bladder and thereby reduce high bladder pressures.
For treatment of high bladder pressures for
This year, we are providing three new features: A Spanish-language
breakout session on therapies for newly diagnosed patients, ED and incontinence sessions, and a lunchtime support session for wives and partners.
YouвЂ™ll be able to participate, too. Time has been allotted for interaction
between the speakers and the audience.
So set aside October 9 now, because you wonвЂ™t want to miss this conference. The cost will be only $15 and that will include lunch, parking, and
eight hours filled with ideas and information about PC. Look for more information at the PCRI Web site: www.pcri.org.
patients who do not respond to medication, an
Interstim вЂњbladder pacemakerвЂќ can be implanted to relax the bladder through electric stimulation. Surgical treatments of stress incontinence
due to sphincter damage following prostatectomy include the Artificial Urinary Sphincter and
the Male Sling Procedure, implants that permit
control of the urethra.
High-Dose Ketoconazole Plus
Hydrocortisone (HDK + HC) (Page 3)
High-dose ketoconazole is an oral anti-PC
agent that is diagnosed in order to lower testosterone levels by blocking various endocrine
pathways. It has also been shown to have direct
cancer killing action on PC cells. HDK has
been studied as a PC drug for almost two
decades, but initially side effects limited its use.
Today, however, it is widely believed that HDK
+HC may be a reasonable treatment approach
for men with PC for whom androgen deprivation therapy was insufficient. A number of
HDK+HC studies have reported significant lowering of PSA levels and/or improvements in
bone pain. The article describes side effects of
HDK and lists drugs that have negative interactions with HDK. The article concludes that HDK
has great potential for the therapy of PC if
appropriate precautions are taken.
вЂњCan You Hear Me Now?вЂќ
Most of what has been published up to this point in Insights has been
directed toward men with prostate cancer. However, we know that
men who are living with prostate cancer are, in most cases, not alone
in their journey with the disease. The partner of the man with prostate
cancer is so important, even critical, in every aspect of this disease, from
diagnosis to researching treatment options and side effects, and recovery. Beginning
with this article dealing with the need for open communication, we intend to follow
up with subsequent pieces addressing issues that we hope will be of interest to the partners of men with prostate cancer.
вЂњThe commitment to communication is essential between couples who are living with prostate cancer and its side effects.вЂќ This message came across loud and clear
at a recent community talk at the USC/Norris Cancer Center in Los Angeles where former
Pennzoil Corp. President and C.O.O. Richard (Dick) Howe, Ph.D. spoke candidly about his
personal experiences with erectile dysfunction (ED) and urinary incontinence that resulted
from a radical prostatectomy for prostate cancer in 1991. Together with his wife, Desiree, who
rounded out the talk from a partnerвЂ™s perspective, it was clear that in spite of the many challenges they have faced throughout their years together, they have a satisfying, healthy relationship mainly because of their commitment to openly communicate with each other.
(continued on page 2)
вЂњCan You Hear Me, Now?вЂќ
continued from page 1
In her book, His Prostate and Me: A Couple
Deals with Prostate Cancer (Winedale Publishing), Desiree Lyon Howe draws upon personal
experiences and lends an impassioned wifeвЂ™s perspective on the journey with her husband and
prostate cancer, ED and urinary incontinence.
Both were widowed at the time they met and
soon discovered they shared many common
interests (including medicine), although Desiree
confessed that DickвЂ™s
idea of inviting her over
to watch вЂњa really exciting videoвЂќ (A Radical
Prostatectomy) almost
ended their budding
romance. She soon
learned that a relationship with Dick
meant not only
learning everything
there is to know
about prostate cancer, but also recognizing and sharing his drive to
communicate with other men the importance of
testing and being educated about the disease.
Desiree points out that while a man is more
likely to feel at ease talking to other men about
his disease and the side effects, he may be less
likely to communicate on an intimate level with
his partner about these issues. She adds, вЂњCommunication is the essence of intimacy, and
women seek and respond to intimacy.
When a man does not use his wife or partner as
a major link in his support system, he generally raises her level of frustration and, in turn,
increases the possibility that she will raise her
own barrier in the relationship.вЂќ
In addition, the differences in the way
men and women communicate can add
even more of a challenge to communicating
successfully. вЂњMen communicate in a less
empathetic manner than women, probably as
a means for them to maintain their sense of
control and competency or give others the
appearance that they are capable individuals,вЂќ
whereas вЂњmost women by nature pull back
from confrontational issues. When this happens, honest communication goes by the wayside and is often difficult, if not impossible to
regain,вЂќ Desiree says.
If your man doesnвЂ™t communicate his concerns and fears to you, there is a chance you
may begin to feel inadequate, rejected,
unattractive, unloved, shut out, and in your
quest to be loving, understanding, and supportive, you may push your man to talk about his
feelings, causing resentment and silence on his
part, the opposite outcome you hoped to
achieve. You may expect your man to know
whatвЂ™s on your mind without having to tell him;
he may expect you to know how he feels with-
вЂњWhen a man does not use his wife
or partner as a major link in his
support system, he generally raises
her level of frustration and, in
turn, increases the possibility that
she will raise her own barrier in
the relationship.вЂќ
out having to express it. These expectations can
lead to feelings of mistrust, anger, anxiety,
depression, grief, embarrassment, shame
and frustration in both of you. Conversely,
good communication can lead to intimacy on
many levels: emotional, spiritual, mental
and physical.
Though a diagnosis of prostate cancer or
side effect like ED or incontinence can strain a
relationship, it often times can turn into a positive experience that strengthens and adds intimacy to a relationship. Desiree also emphasizes
that a вЂњcoupleвЂ™s basic relationship, including
their ability to openly communicate,вЂќ is the
most important factor in dealing with these sensitive issues. Finally, when talking with your
partner, keep in mind her belief that вЂњcommunication is always a major part of the
answer to most every problem.вЂќ
If you would like to comment on this article,
suggest a topic for a future article, or share a story (anonymously) that might benefit partners or
couples living with prostate cancer, please write
to Diana Garnand at [email protected].
Points to Ponder
How do you develop good communication in your relationship?
вќЏ Be sensitive. Understand that your man may
avoid talking to you about his ED or incontinence because he is embarrassed or ashamed.
вќЏ Be direct. Are you saying the same thing
differently? Does it take you a paragraph to say
the same thing that he can express in one
sentence?
вќЏ Be encouraging. Encourage вЂњrealвЂќ communication and openness and help him realize that
avoiding difficult subjects will not make the
problem go away, but will compound them.
вќЏ Recognize your differences. Pushing him to talk
about his problems may cause him to tune out;
being empathetic and understanding of his
feelings while gently reminding him that you are
concerned may yield better results.
вќЏ DonвЂ™t dump. Rather than react or unload when
he opens up to you, give him a chance to
express himself and his concerns without
interrupting.
вќЏ Find a middle ground. Reach a level of
understanding that satisfies each of you, and
know when to stop or move on.
вќЏ Talk it out. Remind him in subtle ways of the
importance of вЂњtalking throughвЂќ your dilemma
and how this can help create more intimacy
between you.
вќЏ Summarize. Review what he shared with you so
that he feels understood. Ask him to do the
same for you.
2
High Dose Ketoconazole Plus Hydrocortisone (HDK+ HC)
Prepared by the PCRI Helpline Staff with oversight by Richard Lam, M.D.
High-dose ketoconazole (HDK) is an oral
broad-spectrum anti-prostate cancer (PC)
agent that has testosterone lowering effects
through its abilities to decrease both testicular
and adrenal production of androgens by blocking various endrocrine pathways. Thus, it is a
form of androgen deprivation therapy. More
specifically, HDK is classified as a P450 enzyme
inhibitor and has also been shown to have
direct cell killing action on PC cells.2 As a result,
HDK plus hydrocortisone (HC), which is needed
to replace natural cortisol production that may
be lost when Nizoral is used, may be a reasonable treatment approach for men with prostate
cancer (PC) for whom primary androgen deprivation therapy (ADT) was insufficient.
The treatment of systemic prostate cancer is
often a progressive selection of therapies based
on the cancer cell population. ADT is usually
the first treatment selected when the PC is diagnosed as systemic. The object of ADT is to reduce
the androgens that are promoting PC growth.
Primary ADT usually consists of an LHRH agonist such as Lupron (leuprolide acetate) or
Zoladex (goserelin acetate) plus an anti-androgen such as Casodex (bicalutamide) or Eulexin
(flutamide). And some physicians add a third
drug called a 5-alpha reductase inhibitor, either
finasteride (Proscar) or dutasteride (Avodart), to
inhibit the production of dihydrotestosterone
(DHT). If PC tumors are primarily comprised of
вЂњandrogen-dependentвЂќ cells, ADT may control
tumor activity for an extended period of time.
Proper management of ADT requires measuring the testosterone to assure that a castrate level is maintained. This concept was covered in
detail in the August 2001 and October 2001
issues of Insights.
* AG is a second-line hormonal androgen blocker
that is now used only rarely in the U.S.
PC that no longer responds to ADT is
sometimes mistakenly identified as вЂњhormone
refractoryвЂќ while in reality it often responds to
secondary hormonal manipulations such as
HDK, Aminoglutethimide (AG)* or the synthetic estrogen DES (diethylstilbestrol). This
article is devoted to the overview and discussion of HDK+HC.
Since PC is so unique in its inherent sensitivity to changes in levels of male sex hormones, trying HDK plus HC may be an option if it becomes
clear that primary ADT is no longer fully effective
in suppressing testosterone. HDK can rapidly lower serum testosterone to castrate levels. For example, HDK administration results in a decline in
serum testosterone within 30 minutes and a 90%
reduction by 48 hours3 (see Figure 1).
HDK also has a direct cell-killing effect on
the prostate cancer cell (see Figure 2). In vitro
tests of two human cell lines of androgen-independent prostate cancer, PC-3 and Du-145,
showed that HDK had direct cell-killing effects
at serum values that were clinically attainable
(1.1 to 10.0 mcg/ml).2
in the pre-PSA era and in the current era of
using PSA as a surrogate biomarker of disease
response. In the pre-PSA era, Pont et al reported
an 88% decrease or disappearance of pain in 17
previously untreated men with metastatic
PC. Two of these patients remained in complete
remission with no manifestation of disease after
30 months of treatment.4
Muscato et al reported on 21 patients treated with HDK and HC that were considered to be
hormone-refractory. Seven of 21 patients, or
33%, had a greater than 90% fall in PSA with
six of these seven maintaining remissions lasting greater than 12 months (range 14-35+
months).5
In a 1997 paper, Small et al reported the
results of HDK + HC therapy in men with progressive disease after ADT and after anti-androgen withdrawal. Of 48 evaluable patients, 30
(62%) had a PSA decrease of greater than 50%
for at least eight weeks while 23 of these (48%)
had a decrease in PSA of greater than 80% also
maintained for at least eight weeks. The PSA
dropped to 0.3 ng/ml or less in five patients for
3+, 4+, 5+, 7+ and 10+ months. These same
Results Using HDK + HC in
five patients had PSA values of 22, 47, 15, 488
Patients with PC
and 6.7 ng/ml, respectively prior to initiating
Published clinical trials of HDK involved studies
HDK + HC. For all 48 of these patients, the median PSA decrease was 79% (range 0Figure 1. Testosterone decline
99%). The median duration of
after HDK administration.
600
562
response was 3.5 months with 23 of
Testosterone Level
500
the 48 patients having ongoing
% Reduction
400
351
responses (range 3.2+ months to
330
300
12.3+ months). No difference was
201
180
200
136
seen in response rates despite the pres75.8 53 90.5
67.9
64.2
100
58.7
37.5
ence or absence of an anti-androgen
0
0
0.5
2
4
6
25
48
withdrawal response (AAWR). The
Hour of treatment
median survival of all patients had
not been reached at 6+ months.6
3
Testosterone ng/dl
Ketoconazole, the generic name for
NizoralВ®, is a synthetic antifungal agent
used to treat fungal infections since the
1970s. When given at traditional doses of 200400mg/day to treat fungal infections, it was noted to temporarily decrease testosterone and
adrenal androgen levels. Higher doses (8001200mg/day) produced a longer hormone
blockade with bound and free testosterone
equally decreased. The concentration of ketoconazole appeared to be the reason for the more
complete blockade.1
Figure 2. Effect of ketoconazole on DU-145 and
PC-3 androgen-independent cell lines.2
250
Mean Colony Number
Overview
204
200
200
138
150
100
50
0
PC-3
DU-145
84
47
45
31
Untreated
0.1
24
15
12
8 5
1.0
2.5
5
10
Ketoconazole Concentration ug/ml
3
0 0
50
In another 1997 abstract, Small
et al described a treatment of 20
patients with simultaneous AAW and
HDK + HC. Fourteen of these
patients (70%) had a greater than
70% drop in their serum PSA level,
and in 10 patients (50%) the decline
in PSA level was greater than 80%
compared to baseline levels. Six of
the 10 were still responding after 2+
to 9+ months.7
(continued on page 4)
High-dose Ketoconazole Plus Hydrocortisone (HDK+ HC)
PCRI co-founders Scholz and Strum conducted a 60-patient study that concluded that
вЂњprolonged response with ketoconazole is far
more common in HRPC patients if treatment is
initiated before the baseline PSA (bPSA) rises
above 10.вЂќ The results showed that patients with
a bPSA of less than or equal to 10 had a median duration of response (MDR) of 25 months.
Patients with a bPSA of greater than 10 had an
MDR of only four months.8
Decrease in bone pain has frequently been
reported with HDK therapy. In 1984, Trachtenberg published his findings of 13 patients who
completed at least 6 months of treatment with
HDK 400mg every 8 hours. HDK greatly reduced
the need for analgesics, serum prostatic acid
phosphatase levels dropped to normal and
testosterone levels were reduced. The side effects
in this group were reported as limited.9
In 1988, 22 Stage D2 patients were followed
at MD Anderson Hospital in Houston. In spite of
previous androgen deprivation therapy, 16 of
the 22 patients reported pain as a significant
part of their clinical picture prior to HDK. Of
these patients, 13 (81%) noted improvement in
bone pain for 1-8 months (mean three
months). Subjective improvement in bone pain
was also reported by others using HDK in hormone refractory PC patients.10 Since bone pain
can affect quality of life, a trial of HDK with HC
may be appropriate if bone pain is a part of the
clinical picture for those whose PC has progressed while on ADT.
High-Dose (e.g. 400 mg, three times a day)
ketoconazole is not the only approach. In 2002,
Harris et al published a study with LDK (LowDose Ketoconazole) that included 28 patients
with progressive prostate cancer despite castrate
levels of testosterone and ongoing testicular
androgen suppression. Treatment consisted of
low dose ketoconazole (200 mg. three times daily) and oral replacement doses of hydrocortisone
(20 mg. every morning and 10 mg. at bedtime).
Thirteen (46%) of the 28 patients had a PSA
decrease of more than 50%. The authors concluded: вЂњThe regimen of low dose ketoconazole with replacement doses of hydrocortisone is well tolerated and has moderate
activity in patients with progressive androgen independent prostate cancer.вЂќ11 This
continued from page 3
treatment may be a reasonable option for those
who cannot tolerate larger doses of ketoconazole, i.e. HDK, but who may benefit from a secondary hormonal manipulation. LDK is certainly of interest for further investigation.
Administration Guidelines for
HDK + HC
HDK is initially prescribed at a dose of 200 mg
three times a day for one week, then the dose is
increased to 400 mg (two tablets) three times a
day thereafter. HC is normally prescribed at a
dose of 20 mg with breakfast and 10 or 20 mg
with dinner. HC should be taken with food.
If symptoms suggest HC excess (ankle swelling
or diabetes in poor control), the dose may need
to be decreased. NOTE: Do not abruptly discontinue HC. Always discontinue HC by tapering the
dose with the guidance of your physician. This
may take several weeks.
Unlike HC, HDK should be taken on an
empty stomach (30-60 minutes before or at
least two hours after food) because HDK
requires acidity for dissolution. Stomach acid
is needed to enhance HDK absorption
(bioavailability) so PC patients take HDK on
an empty stomach so that food there will not
act as a buffer and interfere with the absorption of HDK. Moreover, histamine 2 (H-2)
receptor antagonists (e.g. Zantac, Tagamet,
Pepcid, Axid) decrease HDK absorption by
75%. Proton-pump inhibitors (Prilosec, Prevacid, Nexium) reduce acid even more.
Antacids and Carafate will also interfere with
HDK bioavailability. Many other drugs have
the potential to interfere with the absorption of
HDK by their anticholinergic side effects that
decrease stomach acid (see list below).
If a patient has a medical condition requiring him to lower his stomach acid, taking HDK
with Coca Cola or Pepsi (Diet OK), lemonade,
orange juice, or 1000 mg Vitamin C is a reasonable option to increase absorption of HDK.
Like many medical oncologists using HDK, Dr.
Snuffy Myers does not recommend grapefruit
juice be used in this setting. Grapefruit juice
does not effectively acidify the stomach, and its
impact on ketoconazole has not been documented and may lead to an accumulation of
HDK resulting in toxic drug levels.12 A recent
study done in patients who were taking acidreducing drugs showed a 50% increase in ketoconazole bioavailability when it was taken
along with a carbonated beverage.13
It should also be kept in mind that as people age, they may produce less stomach acid.
This could have an impact on HDK absorption. Therefore, adding 500 mg of asorbic acid
may be wise to avoid this concern. Check with
your physician.
Monitoring Nizoral Blood
Levels
HDK bioavailability (serum Nizoral or ketoconazole levels) can be monitored by a commercially available blood test. Our ability to
assess this biological marker makes HDK therapy unique. Since there are many variables associated with absorption of HDK, a laboratory test
of this nature is invaluable. Pont et al14 and
Heyns et al15 reported on the value of serum HDK
monitoring and their correlation with lowering
androgen levels and clinical response.
Some oncologists have long recommended
a ketoconazole blood level of at least 4.0, which
should be tested at four hours past the morning
dose.16 They also recommend that patients wait
at least three weeks after initiating HDK+HC
therapy to ensure that the drug has obtained
full strength in the blood stream. This theory is
reinforced by the works of Eichenberger17 and
Witjes in 1989.18
Drugs have the potential to interfere with the absorption of HDK.
These include, but are not limited to the following (check with your physician):
Artane (trihexyphenidyl)
Cystospaz (hyoscyamine)
Lomotil (has atropine)
Atrovent (ipratropium)
Ditropan (oxybutynin)
Pro-Banthine (propantheline)
Beelith (has magnesium)
Donnatal (has belladonna)
Robinul (glycopyrrolate)
Bellergal (has belladonna) Levsin (hyoscyamine)
Transderm-V (scopolamine)
Bentyl (dicyclomine)
Urised (has hyoscyamine)
4
Levsinex (has hyoscyamine)
High-dose Ketoconazole Plus Hydrocortisone (HDK+ HC)
It is therefore suggested that after a patient
has been on HDK for three weeks or more, a
Nizoral blood level be obtained at four hours
after the morning dose of HDK. The PCRI
Helpline staff may be able to assist callers in
locating a laboratory that offers this testing.
continued from page 4
ed to unhealthy and even dangerous levels.
Any risk factor for elevated LFTs such as a history of hepatitis or a regimen of other liver-affecting medications should be taken into consideration when using HDK. Patients on HDK should
have liver function tests checked monthly.
Table 1 indicates that skin toxicity is a sigSide Effects
nificant side effect in two of the studies,
The most common side effects are weakalthough a search of the literature does not
ness or lack of strength, gastrointestinal
indicate it to be as common as one would
complaints such as nausea or vomiting, livexpect based on this data. Acquired cutaneous
er toxicity, skin reactions, and a potential
adherence, or Sticky Skin Syndrome seldom
risk from adrenal suppression.
causes sufficient discomfort for therapy to be
It is important to emphasize that any nauwithdrawn.20 However, Sticky Skin Syndrome
sea or loss of appetite a patient may experience
can cause painful physical discomfort in
after initiating HDK + HC usually improves
patients using HDK and has been described as
over time. It is inadvisable for patients on HDK
sitting on a vinyl chair on a hot day while
to self-medicate with acid-blocking medicawearing shorts. It can also result in an uncomtions, antacids, or other over-the-counter (nonfortable adhesion of thighs or under arms.
prescription) items without consulting a physiSmall et al report that the principal side
cian. Because stomach acid is necessary
effects of HDK are related to gastric irritation
for absorption of HDK, use of antacids
leading to nausea and anorexia in at least 10%
will limit HDKвЂ™s effectiveness.
of patients. These side effects are due to mild
Table 1 lists reported side effects from
adrenal insufficiency caused by such high-doses
HDK+HC therapy found in peer-reviewed literaof HDK. Cortisol, a specific type of steroid called
ture. They are displayed in order from most comglucocorticoid, regulates glucose and oneвЂ™s abilmon to least common.
ity to deal with stress and is essential for life. Mild
Of all the side effects, liver damage may be
loss of cortisol production results in fatigue and
the greatest concern. As HDK is being reevaluatnausea. Cortisol is produced in a diurnal pattern
ed for treatment of PC, it has become clearer that
with peaks in the early morning hours gradualliver function test (LFT) abnormalities are mild
ly dropping through the day to lower levels.
to moderate and in most cases return to normal
When stress increases such as with illness,
without intervention. In some patients, howinjury, or surgery, and cortisol is blocked by HDK,
ever, liver function tests can become elevatone can go into shock and die. LifeTable 1.
threatening cortisol deficiency is
Side Effects From HDK+HC Treatment
uncommon for men using HDK for
Polson
Small
Small
PC, but mild adrenal cortisol defi199519
19977
19976
ciency is common. The use of
Patients in Study
39
20
50
hydrocortisone appears to diminish
Skin toxicity
29%
these side effects and may even
(Sticky skin only)
enhance HDKвЂ™s ability to reduce
Skin toxicity
20%
testosterone for steroids have long
(Sticky skin, easy bruising,
been known to have androgen
dryness)
deprivation properties and are often
Elevated liver enzymes 10%
4%
employed in the treatment of PC.
Nausea/vomiting
15%
10%
It has been suggested by some
Gynecomastia (Breast
15%
that
those taking HDK with HC carenlargement and tenderness)
ry
an
ID card or Medic Alert bracelet
Fatigue
10%
6%
indicating the possible need for supEdema
6%
plementary doses of HC during periRash
4%
ods of stress. Ask your pharmacist or
Anorexia
2%
doctor how to obtain this card.
5
Intolerance of HDK side effects such as nausea, fatigue or abnormal liver function tests are
the most common reasons patients stop this
treatment. Fortunately, AG combined with
hydrocortisone is rarely associated with nausea
or liver function abnormalities, and it can be
effectively substituted for HDK in some patients.
Drug Interactions and
Precautions
Note: the following is not an all-inclusive list of
all drugs that may interact with HDK. Make
sure that the administering physician has a
complete list of your current medications and
supplements. Also, check a current version of
the PhysicianвЂ™s Desk Reference (PDR) for personal validation.
HDK should not be taken with
Antihistamines: Seldane (terfenadine),
Claritin (loratadine) and Hismanal (astemizole). (Although Hismanal has been withdrawn from the U.S. market, patients may still
have access to it.): HDK significantly increases
the blood levels of these drugs, which can potentially cause serious cardiovascular side effects.
Oral anti-diabetic medications: Diabinese (chlorpropamide), Glucotrol (glipizide), DiaBeta, Glynase or Micronase
(glyburide), Glucophage (metformin) and
Tolinase (tolbutamide): HDK may increase
the blood sugar-lowering effects of these drugs
and result in severe hypoglycemia.
Other types of medications: Propulsid
(cisapride): Propulsid is a medication that promotes gastrointestinal tract motor activity.
When given with HDK, Propulsid may cause
lethal cardiac rhythms. Although Propulsid is
no longer generally available in the U.S.,
patients may still have access to it.
WARNING: HDK should not
be taken with alcohol!
Concurrent HDK and alcohol-containing
beverages may cause an вЂњAntabuse reactionвЂќ (skin flushing, rash, swollen legs,
nausea, vomiting and headache).
Drugs that may need dose
changes if HDK is taken
concurrently
Anticoagulants (blood thinners): e.g.
Coumadin (warfarin): HDK increases the
blood-thinning effect of Coumadin which may
(continued on page 11)
The Linkage Between Obesity and Prostate Cancer
Introduction
There are a number of plausible biological mechanisms whereby obesity could
promote the development and progression of cancer.1 The evidence for a connection
between obesity and common forms of cancer is
drawn from studies of populations, animal
experiments, and limited clinical research on
humans. However, this research largely provides
biological proof of principle. With the exception
of non-melanoma skin cancers, where a low fat
diet led to a reduced incidence of tumors and
modest weight loss,2 there are no definitive
large-scale clinical intervention studies
demonstrating that weight loss or dietary
changes reduce the incidence of cancer.
Nonetheless, there is a broad base of evidence that
is sufficient to warrant advising cancer survivors
to follow current dietary advice to achieve and
maintain a healthy body weight by increasing the
amount of fruits, vegetables, and whole grains in
the diet while reducing fats. The balance of this
article presents an overview of this evidence.
Statistical Evidence
There is a worldwide epidemic of common
forms of cancer including prostate cancer in
those countries and socioeconomic groups
within countries eating a so-called Western Diet.
This chaotic вЂњdietвЂќ is characterized by a dietary
pattern rich in fat, sugar, and red meat, but poor
in fiber, fruits and vegetables.3 Since age is the
primary risk factor for cancer, all such associations are based on age-adjusted incidences that
can be up to five times higher in so-called high
risk countries (e.g. U.S.) compared to low risk
countries (e.g. Japan). Moreover, individuals
migrating from low risk to high-risk countries
increase their risk of cancer substantially within a single generation.4
Obesity is also associated with a number of
common forms of cancer.5 These data have
implicated environmental and lifestyle factors
including diet in the etiology of cancer. There is
also evidence that obesity is associated with an
increased rate of progression of cancer following initial treatment.6 There is an ever-increasing population of cancer survivors and an
increasing incidence of obesity. If patients with
diagnosed cancer who have survived initial
treatment are treated for obesity, it may improve
outcomes and increase median survival. Even if
these efforts had no effect on any remaining
*Paracrine is a form of signaling in which the target
cell is close to the signal-releasing cell.
cancer cells, treating cancer survivors for obesity improves their quality of life and reduces the
risk of other chronic diseases including heart
disease and diabetes.
Common Biological Processes
Obesity, characterized by excess fatty tissue, has
been shown to increase the risk for development
of several common cancers. There are a number of biological processes common to these two
conditions that could lead to a causal interrelationship. Many hormones involved in obesity
also play a role in the initiation and promotion
of cancer both at a cellular, paracrine*, and systemic level.7 In developed countries, the most
common forms of cancer (including lung cancer, breast cancer, prostate cancer, pancreatic
cancer, ovarian cancer, uterine cancer, kidney
cancer and gallbladder cancer) are epithelial
cell cancers. And interactions between epithelial
and stromal components within the tissue (as
well as hormones reaching the organ via the
circulation) may play a role in stimulating
tumor development and growth.
There are at least four different mechanisms by which increased hormone secretion
may promote cancer development. First, obesity
leads to increased production of growth-promoting steroid hormones that can bind to
nuclear receptors in hormone-dependent tumor
cells. For example, estrogens8 are produced in
excess amounts through aromatization of
adrenal androgens by adipose stromal tissues in
peripheral fat tissues. Second, free hormone levels can be affected by hormone-hormone interactions as in the case where upper body obesity
is associated with reduced Sex Hormone Binding Globulin levels leading to increased free levels of circulating estrogens and testosterone.9
Third, steroid hormone action can trigger
increased oxidant-stress-promoting cell proliferation and DNA damage.10 Androgens have
been demonstrated to increase oxidant stress in
prostate cancer cells, and oxidant defense
mechanisms have been shown to be impaired
early in the cancer process.
Finally, obesity can increase the production
of paracrine factors and hormones which stimulate the production of steroid hormones in
cancer tissue through interactions between stromal and epithelial compartments in tissues.
Many of these paracrine factors are cytokines
produced by both fat cells and white blood cells.
Obesity is associated with increased circulating
levels of cytokines, and these levels are reduced
with weight loss.11 The fat cell, which is the
source of many of these so-called adipocytokines (see Figure 1), may play a significant
role in the ability of fat tissue to preserve
immune resistance to infections. It has long
been recognized that malnutrition is associated
with multiple impairments of immune function including impaired T-helper cell function.
Hence, the ability of fat to store calories provides
a separate important function to protect
immune defenses.12 Today, cancer and heart disease are replacing infectious diseases as the primary cause of death, as obesity becomes more
common in developing countries. It is possible
that the increased cytokine secretion observed in
obesity is simultaneously having a beneficial
Figure 1. Adipocytokines and Other Fat Cell Products.
Cholesterol Transfer
Protein (CETP)
Phosholipid Transfer
Protein (PLTP)
Lactate
Prostaglandin
Angiotensinogen
Leptin
Prostacyclin
Adiponectin
Monobutyrin
Galectin-12
Free Fatty Acids
TNF-=
Plasminogen Activator
Inhibitor (PAI-1)
Adipsin (ASP)
IL-6
Lipoprotein
Lipase (LPL)
6
(complement (3a;D)
David Heber, MD, PhD, FACP, FACN, Professor of Medicine and Director, UCLA Center for Human Nutrition
effect on infectious disease resistance while at
the same time increasing the risk of cancer.
Information Specific to
Prostate Cancer
The diagnosis of prostate cancer has improved
in recent years due to the development of the
PSA test, which detects prostate cancer before it
is physically palpable as a mass on rectal examination.13 Approximately 180,000 American
men were diagnosed with prostate cancer in
2000.14 Prostate cancer develops as a result of
both inherited and environmental factors. It is
associated with aging, and it occurs in a latent
or clinically inactive form in 30% to 40% of men
by age 30 to 50 years and in 75% of men by age
80.15,16 Because latent or clinically inactive cancers were not as effectively diagnosed prior to
the development of the PSA test, some uncertainty exists in predicting the behavior of
prostate cancer after diagnosis.
The cause of this disease is not fully understood, but a family history, the effects of androgens (like testosterone) and other hormones,
and environmental and dietary factors may all
be involved. The international variations in the
rates of prostate cancer are considerable. (See
Figure 2.) The county of Qidong in China has
the lowest recorded incidence rate, 0.5 per
100,000 men. By comparison, Sweden has a
rate of 55.3 per 100,000 men and the U.S. has a
rate of 102.1 per 100,000 men.17 Of course, diagnosing silent cancer by blood PSA increases the
statistical incidence of the disease because more
clinically silent cancers are diagnosed. Global
differences in incidence are probably not due to
inheritance. If individuals with the same
inherited genes are raised in two different environments, the risk of prostate
cancer is associated with the country in
which they are raised.18
An American Cancer Society survey of
750,000 individuals demonstrated that being
obese increased the risk of prostate cancer.19
Among the various nutritional factors examined, per capita total fat consumption correlates
with increased prostate cancer incidence in
cross-national studies. In a population-based
case-control study of prostate cancer among
blacks, whites and Asian-Americans in Los
Angeles, San Francisco, Hawaii, Vancouver and
Toronto, a positive statistically significant association of prostate cancer risk and total fat
studies have found an association between
prostate cancer and dietary fat; however,
none has shown a negative correlation.
Figure 2. Prostate cancer incidence
around the world.
United States 102.1
Latent vs. Clinically Active
Prostate Cancer
Sweden 55.3
China .5
(Qidong County)
0
20
40
60
80
100
120
Per 100,000 Men
intake was found for all ethnic groups combined. This association was attributable to energy intake from saturated fats.20 In Japan, an
increase in prostate cancer risk has been noted
as the per capita intake of dietary fat has
increased.21 In Hawaii, a correlation was found
between saturated fat intake and prostate cancer incidence. A representative sample of over
4,000 adults at least 45 years of age from the
five main ethnic groups in Hawaii were interviewed regarding their diet, and multiple
regression analysis was used to assess the statistical relationship between ethnic-sex-specific
dietary intakes and corresponding populationbased cancer incidence rates. Significant positive associations were found for prostate cancer
with fat intake from saturated and animal
sources, and for animal protein intake.22 In the
U.S., counties with higher prostate cancer incidence have higher per capita fat intake.5
Using questionnaires that ask how often a
particular food is normally eaten, scientists
have found clues to the association of dietary fat
with cancer. In a retrospective study by West et
al23 and a prospective study by Giovannucci et
al,24 the more aggressive prostate cancers in
patients were significantly correlated with high
fat intake. In the Giovannucci study, those individuals eating the highest amount of meat had
a risk of developing prostate cancer 2.64 times
that of those eating the least. The course of
prostate cancer may also be affected by fat
intake. Kolonel et al25 found a significant relationship between dietary fat and prostate cancer
mortality in Hawaiian men 70 years and older.
In addition, several studies have demonstrated
a positive association between saturated fat
intake from meat and dairy products and
prostate cancer.26-31 Other factors in the diet may
enhance or diminish the risk for prostate cancer. Several retrospective and prospective
7
Approximately 60% of all men have latent or
clinically silent prostate cancer, and the incidence of this latent form is the same in the United States and Japan.32 These estimates are based
on autopsies of men who die for reasons other
than prostate cancer. At the same time, clinically significant prostate cancer is much more
common in the United States than in Japan.
When Japanese men migrate to the United
States, their incidence of clinically detected
prostate cancer rises within one generation.
These facts suggest that nutrition and
lifestyle practices in lower-risk countries
suppress the growth of prostate cancer so
that it remains small and confined and is
rarely diagnosed clinically.
The Effects of Aging
Prostate cancer is a disease associated with aging
and obesity. It has been said that if you live long
enough you will have prostate cancer, and over
90 percent of men over the age of 90 have
detectable carcinomas in prostatic tissue. Men
who have premature accidental deaths are found
to have precancerous lesions such as prostatic
intraepithelial neoplasia (PIN) in their prostate
glands if they are between 40 and 60 years of age.
Above 60 years of age, foci of prostatic cancer are
found in addition to PIN lesions. Also commonly associated with increasing age is a shift in the
pro-oxidant-anti-oxidant balance of many tissues toward a more oxidative state. Recently, foci
of proliferative inflammatory atrophy (PIA) have
been found in prostatic cancer biopsy specimens.
While the DNA in PIN and cancerous lesions
have multiple abnormalities, the DNA in the PIA
lesions is normal.
Given the common occurrence of prostatitis,
both clinical and sub-clinical, it has been
hypothesized that the prostate gland with aging
undergoes repeated inflammation leading to
DNA damage, mutation, and ultimately the formation of precancerous and cancerous lesions.
African-American men have a significantly
higher incidence of prostatic cancer compared to
Caucasian men and have higher levels of IGF-1
and androgens at puberty. It has been proposed
(continued on page 10)
Treatment Options for Post-Prostatectomy Incontinence
Loss of bladder control (urinary incontinence) after prostate surgery is a
devastating complication, which has a
significant negative impact on quality
of life. When urinary incontinence persists
after radical prostatectomy, appropriate bladder
testing called urodynamics can evaluate the
function of the bladder and sphincter (valve)
muscle to determine the exact cause of the postprostectomy incontinence (ppi). Normally, as
the bladder fills to capacity, there is very little
change in bladder pressure and the sphincter
remains closed allowing the man to stay dry.
When incontinence occurs following prostatectomy, this normal balance of bladder and
sphincter function is disturbed.
Our research1 has defined three main causes of ppi based upon urodynamic findings in
men with ppi:
1. High pressure (with вЂ�spasmsвЂ™ of the
bladder) developing in the bladder
as the bladder fills (50% of men
with ppi). These bladder spasms may
cause urge incontinence, frequent
urination, and sometimes loss of urine
at night.
2. Damage to the sphincter muscle
(35% of men with ppi). This damage
results in stress incontinence with loss of
urine during coughing, straining, or
vigorous physical activity.
3. A combination of bladder malfunction and sphincter damage (10% of
men with ppi). Men with this combined
problem usually experience вЂњmixed
incontinenceвЂќ symptoms with a combination of both urge and stress
incontinence.
With treatment directed by the urodynamic
testing, the majority of men are able to experience significant improvement in their urinary
control. When the main problem is high bladder pressures, medications to relax the bladder are usually effective. These medicines (generally known as anti-cholinergics) include
Ditropan XL, Detrol LA, the Oxytrol patch, and
imipramine. Both Ditropan and Detrol are oral
medications that are taken once daily. These
medications use a вЂ�time releaseвЂ™ mechanism to
maintain adequate blood levels of the drug to
relax the bladder and eliminate вЂ�bladder spasmsвЂ™
over 24 hours. Side effects of these medications
include dry mouth, constipation, and sometimes
blurry vision. These drugs should not be used in
patients with narrow angle glaucoma or in men
who do not empty their bladder well. The Oxytrol
patch sends the medication to relax the bladder
through the skin. This patch is changed twice
per week and may have fewer side effects than
the oral medications.
Interstim вЂњBladder PacemakerвЂќ
When the usual medical treatments to lower
high bladder pressures are not successful, the
Interstim вЂњbladder pacemakerвЂќ may be an
excellent alternative. This treatment
involves a two-stage approach with both
stages performed under local anesthesia as
an outpatient procedure. The first stage
involves placing a special stimulation electrode next to the main nerve that controls
the bladder. The patient then wears an
external stimulation box for 7-10 days as a
вЂњtest stimulationвЂќ to evaluate the response
of the bladder to the electrical stimulation
to вЂњrelaxвЂќ the bladder. When a good
response is obtained, we proceed with the
second stage of the procedure, which
involves implantation of an internal вЂ�pacemakerвЂ™ that is attached to the stimulation
electrode and programmed through the
skin. Overall approximately 50% of patients
respond to the first stage trial of test stimulation. When we proceed with the second
stage implant, about 85% of patients have an
excellent response. Thus, use of the Interstim
вЂњbladder pacemakerвЂќ is an effective treatment
option for those patients who have high-pressure
bladder dysfunction who do not respond to the
usual forms of medical treatment.
Options for treatment of sphincter damage
include biofeedback, injection therapy (which is
generally not successful), the artificial urinary
sphincter, and more recently the male sling procedure. Those men with вЂњmixedвЂќ bladder and
sphincter malfunction will undergo initial
treatment to improve their bladder function (i.e.
lower their bladder pressures) followed by treatment to address the weak sphincter.
The Artificial Urinary
Sphincter (AUS)
Perfected over the last 20 years, the artificial urinary sphincter is a device implanted into the
body to correct stress incontinence in men with
significant sphincter damage. The AUS has
three components: a cuff that helps close the
8
urethra, a pump placed inside the scrotum, and
a pressure regulating balloon which is placed in
the lower abdomen (see Figure 1). When the
man wants to urinate, he squeezes the pump in
the scrotum, which opens the cuff around the
urethra. Automatically, after 3-5 minutes, the
fluid returns into the cuff allowing the cuff to
close. After the device is tested during surgery,
the cuff is вЂњlockedвЂќ open, and is only activated
when swelling around the pump is gone (usually about 4-6 weeks after surgery).
Figure 1.
Artificial Urinary
Sphincter in place.
With the current model of the AUS, longterm patient satisfaction has been excellent with
less that a 15% mechanical malfunction rate at
7.5 years after implantation of the device.2
Despite these excellent long-term results, however, some men are hesitant to have this prosthetic device placed. For these men, as well as
for those with more minor degrees of ppi or for
men who do not have the manual dexterity to
squeeze the pump in the scrotum, the male
sling is a promising alternative.
Male Sling Procedure
Over the last two years, the male sling procedure
has become a viable treatment alternative for
men with ppi due to sphincter damage causing
stress incontinence. The surgical procedure to
implant the sling takes about one hour and can
be done either on an outpatient basis or with an
overnight hospital stay. The purpose of the
вЂњslingвЂќ is to compress the urethra and help
eliminate loss of urine with coughing, sneezing,
or vigorous activity.
Gary E. Leach, MD, Director, Tower Urology Institute for Continence, Los Angeles
Figure 2. Placement location for six bone
screws that secure the male sling in position.
The sling is placed via an incision
between the scrotum and rectum. After
exposing the pelvic bone on each side,
six titanium bone screws are placed into
the pubic bone (three screws on each
side). A permanent suture is attached to
each bone screw (see Figure 2). These
sutures are then passed through the
material used to create the sling, which
will compress the urethra. The material
used for the sling may be cadaveric tissue, processed non-human tissues, or
synthetic materials. The author prefers
to use commercially available nonfrozen cadaveric fascia lata.
Three sutures on one side are passed through
one edge of the sling and tightly tied. The three
sutures on the other side of the pubic bone are then
passed through the sling and tied to create closure
of the urethra at a pressure of 60cm water pressure.
This pressure is confirmed by running sterile fluid
backward into the urethra at 60cm water pressure
and confirming that this fluid perfusion stops
when the sling is tightened down (see Figure 3).
The incision is then closed. A catheter is usually left
in place for 24 hours with most men being able to
urinate with good control immediately after the
catheter is removed.
Thus far, the results with the male sling
have been encouraging. In one series of men
undergoing the male sling, 40% of men are
completely dry, 40% are significantly improved,
and 20% are considered failures. Of those men
who did not respond to the male sling, an artificial urinary sphincter could be considered as a
second alternative.
Summary
Recent advances in the evaluation and treatment of men with incontinence following
prostate surgery have allowed many men to
regain their urinary control and improve their
quality of life. The male sling is a significant
advance in how we treat ppi. In well-selected
candidates, the male sling is an effective treatment option for many men. вќЏ
References
1. Leach G, Trockman B, Wong A, et al: Post-prostatectomy incontinence: urodynamic findings and treatment outcomes. J. Urology 155:1256, 1996.
2. Haab F, Trockman B, Zimmern P, and Leach G: Quality of life and continence assessment of the artificial urinary sphincter in men with minimum 3.5 years of followup. J. Urology 158:435-439, 1997.
Illustrations provided courtesy of American
Medical Systems, Inc.
Figure 3.
Male sling in position compressing the urethra.
HDK continued from page 11
11. Harris KA, et al: Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer. J Urol;168(2):542-5 Aug 2002.
12. Myers CE: Ketoconazole (Nizorol). Prostate Forum 6-4:1-4, April 2001.
13. Chin T, et al: Ketoconazole вЂњgoes better with cokeвЂќ. Mycology Observer 12:5
1994.
14. Pont A, Graybill JR, Craven PC, et al: High-dose ketoconazole therapy and
adrenal and testicular function in humans. Arch Intern Med 144:2150-3,
1984.
15. Heyns W, Drochmans A, van der Schueren E, et al: Endocrine effects of
high-dose ketoconazole therapy in advanced prostatic cancer. Acta
Endocrinol 110:276-83, 1985.
16. Strum SB: High dose ketoconazole is effective against androgen-dependent
and androgen вЂ“independent prostate cancer and is synergistic with
chemotherapy. PCRI Insights 4-3:7; Aug 2001.
17. Eichenberger T, Trachtenberg J, Chronis P, et al:Synergistic effect of kenoconazole and anti-neoplastic agents in hormone-independent prostatic
cancer cells. Clin Invest Med;12(6): 363-6, Dec 1989.
18. Witjeset al. Ketoconazole high dose is management of hormonally treated
patients with progressive metastatic prostate cancer. Urology 33: 411-15:
1989.
19. Polsen JA, Cohen PR, Sella: Acquired cutaneous adherence in patients with
androgen-independent prostate cancer receiving ketoconazole and doxorubicin: medication-induced sticky skin. J Am Acad Dermatol: 32
(4):571-5 1995.
20. Ketoconazole in advanced prostate cancer: have tolerability concerns been
overstated? Drug and Their Perspect 15 (4): 11-13, 2000 В© 2000 Adis
International Limited.
21. Wang YG, Yu CF, Chen LC, et al. Ketoconazole potentiates terfenadineinduced apoptosis in human Hep G2 cells through the inhibition of
cytochrome p450 3A4 activity. J Cell Biochem 87(2):147-59; 2002.
22. Chen TC, Holick MF. Vitamin D and prostate cancer prevention and treatment. Trends Endocrinol Metab. 2003 Nov; 14(9):423-30.
23. Beer TM. Development of weekly high-dose calcitriol based therapy for
prostate cancer. Urol Oncol. 2003 Sep-Oct;21(5):399-405.
How to
Contribute to
If you would like more information or if
you have a question, contact Dr. Gary
Leach at: Email: [email protected]
Phone 310-854-9898 / Fax 310-854-6993
www.towerincontinence.com
PCRI
You can help PCRI continue its mission of providing the latest
information and education about prostate cancer through
programs, such as this newsletter, in the following ways:
вЂў Direct Donation: cash, check, or credit card; stock or real estate
вЂў Memorial and Gift in Honor Contributions: Honoring someone you
care about with a memorial or commemorative gift
вЂў Planned Giving: Naming PCRI in your will or as beneficiary of a life
insurance policy.
Your tax-deductible gift in the form of cash, stocks or real estate
should be made payable to PCRI and mailed to:
Prostate Cancer Research Institute (PCRI)
5777 W. Century Blvd., Suite 800, Los Angeles, CA 90045
Federal Tax ID Number: 95-4617875
Credit card donations can be made online at: www.pcri.org.
For further information, please contact PCRI at (310) 743-2116, or by e-mail
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Prostate Cancer Research Institute is a non-profit corporation, exempt from federal income taxes under
section 501(c)(3) of the Internal Revenue Code. It has been classified as an organization that is not a
private foundation as defined in section 509(a) of the Code, and qualifies for a maximum charitable
contribution by individual donors.
9
The Linkage Between Obesity and Prostate Cancer
that androgen exposure, which has long been
associated with the development of prostate cancer, may be a means by which the pro-oxidantanti-oxidant balance of prostate cells is altered.
In rats, prostatic cancer can be induced by
prolonged administration of testosterone. The
ablation of androgens has formed the basis for
first-line therapy of metastatic prostate cancer.
It has also been proposed that hormones play a
role in the progression of prostate cancer from
silent to clinically significant forms. Since diet
can influence circulating sex steroid hormones, diet and androgens may alter
prostate cancer biology via common pathways. Urinary levels of androgens and estrogens were decreased in a group of Caucasian
and African American men fed a diet in which
fat content was reduced from 40% to 30% of
total calories.33 A very low-fat, high-fiber diet
has been shown to reduce sex steroid levels in a
.group of normal men34 Therefore, changes in
sex hormones may mediate in part the effects of
diet on prostate cancer growth.
As sedentary men age, they often experience
an increase in fat mass, a decrease in lean body
mass, and a change in hormone levels. These
factors have been shown to increase the risk of
prostate cancer. In a study of Seventh-Day
Adventists, obesity was shown to significantly
increase the risk of fatal prostate cancer compared with ideal weight.35 This association was
also noted in the American Cancer Society's
study of 750,000 individuals.5 With aging, the
prevalence of benign prostatic hyperplasia
(BPH) increases; this is an androgen-dependent
chronic disorder.36
Dihydrotestosterone (DHT) formed from
testosterone in the prostate and in the testes
appears to promote hyperplasia in humans,
dogs and rats. Horton et al37 found increased
levels of circulating DHT in elderly men compared with young men (89 ng/dl vs. 49 ng/dl);
in this study, nearly all the elderly men had
BPH. Since the prostate can convert testosterone
to DHT, some have hypothesized that increased
metabolic conversion of testosterone to DHT
may account for the increased DHT levels in
elderly men. Therefore, the effects of a high-fat
diet on prostate cancer are partially explained
by the changes in hormones resulting from that
diet and by a decreasing lean body mass.38
continued from page 7
In prostate cancer cell lines exposed to
physiological levels of 5 alpha-reductase dihydrotestosterone (DHT) and to the synthetic
androgen R1881, proliferative responses and
changes in oxidative stress were correlated.10
Physiologic levels of androgens are capable of
increasing oxidative stress in androgenresponsive LNCaP prostate carcinoma cells.
The evidence suggests that this result is due in
part to increased mitochondrial activity. Androgens also alter intracellular glutathione levels
and the activity of certain detoxification
enzymes, such as gamma-glutamyl transpeptidase, that are important for maintenance of
the cellular pro-oxidant-anti-oxidant balance.
Conclusion
Although there is no clinical trial data
available to define the benefits of weight
reduction, there is a clear association of
obesity with cancer risk, incidence, or progression for a number of common forms of
cancer. Evidence is much stronger for certain
forms of cancer than others, but clearly, the
endocrine and immune systems may play an
important role in mediating the effects of
increased adiposity on cancer risk based on the
hormones and adipocytokines produced by fat
cells. Many of the changes observed in these systems among obese patient are related but secondary phenomena of unknown significance,
but others may be important in cancer development, promotion, or progression. Abnormalities
in adipocytokine production and action are central to many of the observed metabolic changes
in the obese patient, and may play a role in the
cause and maintenance of the obese state as well
as in associated forms of cancer. вќЏ
References
1. Heber D, Blackburn GL, Go VLW (eds). Nutritional Oncology. Academic
Press, San Diego CA , 1999.
2. Jaax S, Scott LW, Wolf JE, Thornby JI, and Black HS. General guidelines for
a low fat diet effective in the management of nonmelanoma skin cancer.
Nutr. Cancer 1997; 27:150-156.
3. Armstrong B, Doll R. Environmental factors and cancer incidence and
mortality in different countries, with special reference to dietary practices.
Int. J. Cancer 1975; 15: 617-631.
4. Shimizu H, et al. Cancers of the prostate and breast among Japanese and
white immigrants to Los Angeles County. Br. J. Cancer 1991; 63: 963-966.
5. Garfinkel L. Overweight and Cancer. Ann of Int Med. 1985; 103:1034-36.
6. Newman SC, Miller AB, and Howe GR A study of the effect of weight and
dietary fat on breast cancer survival time. Am J Epidemiol 1986; 123: 767.
7. Heber D. The role of nutrition in cancer prevention and control. Oncology 1992;6: 9-14.
8. Nimrod A, Ryan KH: Aromatization of androgens by human abdominal
and breast fat tissue. J Clin Endo Metab 1975;40:367.
9. Kissebah AH, Evans DJ, Peiris A, et al. Endocrine characteristics in regional obesities: Role of sex steroids. In Vague J, Bjorntorp P, Guy-Grand B et al
10
(eds). : Metabolic Complications of Human Obesities. Amsterdam, Excerpta Medica,1985, p. 115.
10. Ripple MO, Henry WF, Rago RP, Wilding G. Prooxidant-antioxidant shift
induced by androgen treatment of human prostate carcinoma cells. J Natl
Cancer Inst 1997; 89: 408.
11. Winkler G, Lakatos P, Salamon F, Nagy Z, Speer G, Kovacs M, Harmos G,
Dworak O, Cseh K. Elevated serum TNF-alpha level as a link between
endothelial dysfunction and insulin resistance in normotensive obese
patients. Diabet Med 1999; 16:207-211.
12. Chandra RK. The nutrition-immunity-infection nexis: The enumeration
and functional assessment of lymphocyte subsets in nutritional deficiency.
Nutr Res 1983; 3:605-615.
13. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined
prostate cancer is increased through prostate-specific antigen-based
screening. JAMA. 1993; 270:948-54.
14. Landis SH, Murray T, Bolden S, Wingo PA. Cancer Statistics, CA Cancer J
Clin. 1998; 48:6-29.
15. Tanagho EA, McAninch JW, editors. 1995. SmithвЂ™s General Urology. Appleton and Lange, Norwalk, CT.
16. Thompson IM, Coltman CA, Brawley OW, Ryan A. Chemoprevention of
prostate cancer. Semin Urol. 1995; 13:122-29.
17. Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, editors. 1997. Cancer Incidence in Five Continents, Volume VII. Scientific Publications #143.
18. Mandel JS, Schuman LM. Epidemiology of cancer of the prostate. Rev Cancer Epidemiol. 1980;1:1-65.
19. Lew EA, Garfinkel L. Variations in mortality by weight among 750,000
men and women. J Chron Dis. 1979; 32:563-76.
20. Whittemore AS, Kolonel LH, Wu AH, John EM, Gallagher RP, Howe GR,
Burch JD, Hankin J, Dreon DM, West DW et al. Prostate cancer in relation
to diet, physical activity and body size, in blacks, whites and Asians in the
United States and Canada. J Nat Cancer Inst. 1995; 87:652-61.
21. Boyle P, Kevi R, Lucchuni F, LaVecchia C. Trends in diet-related cancers in
Japan:A conundrum? Lancet. 1993; 349:752.
22. Kolonel LN, Hankin JH, Lee J, Chu SY, Nomura AMY, Hinds MW. Nutrient
intakes in relation to cancer incidence in Hawaii. Br J Cancer. 1981;
44:332-39.
23. West DW, Slattery ML, Robison LM, French TK, Mahoney AW. Adult dietary
intake and prostate cancer risk in Utah: A case-control study with special
emphasis on aggressive tumors. Cancer Causes Control. 1991;2:85-94.
24. Giovannucci E, Rimm EB, Colditz GA, Stampfer MJ, Ascherio A et al. A
prospective study of dietary fat and risk of prostate cancer. J Nat Cancer Inst
1993; 85:1571-79.
25. Kolonel LN, Yoshizawa CN, Hankin JN. Diet and prostatic cancer: A casecontrol study in Hawaii. Am J Epidemiol. 1988; 127:999-1012.
26. Mettlin C, Selenskas S, Natarajan N, Huben R. Beta-carotene and animal
fats and their relationship to prostate cancer risk. Cancer. 1989; 64:605-12.
27. Snowdon DA, Phillips RL, Choi W. Diet, obesity and risk of fatal prostate
cancer.Am J Epidemiol. 1984; 120:244-50.
28. Kaul L, Heshmat MY, Kovi J, Jackson MA, Jackson AG et al. The role of diet
in prostate cancer. Nutr Cancer. 1987; 9:123-28.
29. Slattery ML, Schumacher MC, West DW, Robison LM, French TK. Food
consumption trends between adolescent and adult years and subsequent
risk of prostate cancer. Am J Clin Nutr. 1990; 52:752-57.
30. Ross RK, Shimizu H, Paganini-Hill A, Honda G. Case-control studies of
prostate cancer in blacks and whites in Southern California. J Nat Cancer
Inst.1987; 78:869-74.
31. Talamini R, LaVecchia C, Decarli A, Negri E, Franceschi S. Nutrition, social
factors and prostatic cancer in a Northern Italian population. Br J Cancer.
1986;53:817-21.
32. Yatani R, Shiraishi T, Nakakuki K, Kusano I, Takanari H, Hayashi T. Trends
in frequency of latent prostate carcinoma in Japan from 1965-1979 to
1982-1986. J Nat Cancer Inst. 1988; 80:683-87.
33. Hill P, Wynder EL, Garbaczewski L et al. Diet and urinary steroids in black
and white North American men and black South African men. Cancer Res.
1987; 47:2982-85.
34. Dorgan JF, Judd JT, Longcope C, Brown C, Scatzkin A et al. Effects of dietary
fat and fiber on plasma and urine estrogens in men: A controlled feeding
study. Am J Clin Nutr. 1996; 64:850-55.
35. Mills PK, Beeson WL, Phillips RL, Fraser GE. Cohort study of diet, lifestyle
and prostate cancer in Adventist men. Cancer. 1989; 64:598-604.
36. Geller J, Albert J. 1982. The effect of aging on the prostate. InEndocrine
Aspects of Aging. (Korenman SG, ed.) Elsevier, New York, pp.137-61.
37. Horton R, Hsieh P, Barberia J, Pages L, Cosgrove M. Altered blood androgens in elderly men with prostatic hyperplasia. J Clin Endo Metab. 1975;
41:793-96.
38. Snowdon DA, Phillips RL, Choi W. Diet, obesity and risk of fatal prostate
cancer. Am J Epidemiol. 1984;120:244-50.
High-dose Ketoconazole Plus Hydrocortisone (HDK+ HC) continued from page 5
require a dosage reduction.
Anti-epilepsy agents: Dilantin (phenytoin):
Dilantin may affect the bodyвЂ™s ability to eliminate HDK and vice-versa, leading to blood level
changes for both drugs that can lead to toxic
symptoms.
Anti-infective agents: Rifamate contains
isoniazid and rifampin: HDK causes adverse
changes (up or down) in the blood levels of isoniazid; Rimactane (Rifampin): significantly
reduces the blood levels of kenoconazole.
Editor:
Review Board:
Charles Bader
Stanley A. Brosman, MD
Mark Scholz, MD
Publisher:
Prostate Cancer Research Institute
Design & Production: Diana Garnand
Prostate Cancer Research Institute
5777 Century Boulevard, Suite 800
Los Angeles, CA 90045
Helpline: (310) 743-2110
Phone: (310) 743-2116
Fax:
(310) 743-2113
E-mail: [email protected]
Web sites: www.pcri.org
www.prostate-cancer.org
Executive Director: Glenn D. Weaver
E-mail: [email protected]
Board of Directors
Chester A. Swenson, President
Chairman, Marketing & Financial Services Enterprises
Jerome Seliger, PhD, Vice President
Professor of Health Administration,
California State University, Northridge
Barry L. Friedman, JD, Secretary
Attorney at Law
T. Kent Graham, Treasurer
Financial Consultant, T. Kent Graham & Associates
Duke K. Bahn, MD
Prostate Institute of America
Stanley A. Brosman, MD
Pacific Urology Institute, Pacific Clinical Research
Brian Gauthier
Executive Vice President, St. Vincent Foundation
Arthur Lurvey, MD
Sleeping pills and tranquilizers: Halcion
(triazolam) and Versed (midazolam): HDK significantly increases the blood levels of both drugs.
Cholesterol-Lowering Agents: Statins: Lipitor (atrovastatin), Lovastatin (mevacor), Pravachol (pravastatin), Zocor (simvastatin), Baycol
(cerivastatin вЂ“ recalled 2001): HDK increases
the amount of the statin in the blood and could
lead to serious muscle disease so the dose of
statin may need to be adjusted.
Other types of medication: Medrol (methylprednisolone): HDK increases the blood levels of
Medrol; Sandimmune (cyclosporine): Sandimmune may affect the bodyвЂ™s ability to eliminate
HDK and vice-versa, leading to changes in the
blood levels of both drugs.
Chemotherapy Agents
HDK is synergistic with some chemotherapy
agents, such as adriamycin. However, HDK
blocks the enzymes that clear Taxol, Taxotere,
Emcyt, vincristine and vinblastine, among others. Specifically, HDK blocks the cytochrome
P450-containing protein, CYP 3A4, which is the
enzyme responsible for clearing 50% of all prescription drugs.21 Recent investigation indicates
this activity may enhance various chemotherapy
agents. For example, a chemotherapy drug is
usually cleared in the liver by cytochrome P450
so the patient does not get the full strength of the
dose he is taking. When HDK is used, P450 is
inhibited so he gets the full strength of this medication. Clinical trials must be undertaken to
prove this, but it does appear that HDK may play
a role in chemotherapy treatment in the future.
Each and every drug given to a patient on
HDK needs to be very carefully evaluated. One
must proceed with extreme caution when using
ketoconazole with chemotherapy agents such as
the taxanes. A dramatic dosage reduction of the
chemotherapy (up to 80%) may be needed.
Medicare Contractor Medical Director
Vitamin D
Jerry Peters
Ketoconazole is an inhibitor of Vitamin D
requiring P450 enzymes for metabolism so men
on HDK may be at risk for a Vitamin D deficiency and bone mass loss. Monitoring serum calcitriol (the active form of Vitamin D) could alert
one to the need for Vitamin D replacement.
Besides bone loss concerns, there is additional significance of low Vitamin D for those
with PC as low Vitamin D is thought to increase
the risk and mortality from the disease.22 In the
lab, the work of Thomasz Beer, MD at Oregon
Health and Science Institute in Portland, Oregon has noted reduction of growth of prostate
MCG Records
Claudia B. Sangster, Esq.
Director of Philanthropy Services, myCFO, Inc.
Mark Scholz, MD
PCRI Co-founder
Prostate Oncology Specialists
The cost of printing and mailing this newsletter
is made possible through a generous grant from
The Life Extension Foundation
P.O. Box 229120, Hollywood, Florida 33022
800-544-4440 www.lef.org/prostate
The opinions expressed in the by-lined articles are those
of the authors and should not be considered opinions of
the PCRI.
В© Copyright 2004. Printed on recycled paper.
11
cancer cells with Vitamin D. He has also done
considerable work with Docetaxel and calcitriol
in Androgen-Independent Prostate Cancer with
promising results related to PC growth and few
if any side effects related to Vitamin D.23
Therefore the addition of calcitriol to Nizoral would address the Vitamin D deficiency and
may further reduce the PSA and slow the growth
of the cancer. (Caution: When taking calcitriol,
check with your physician regarding any calcium or Vitamin D supplements since you may
need to discontinue these.)
Conclusions
HDK + HC is a very active regimen in the management of PC. With its broad spectrum of pharmacological activity, HDK is one of the most
active agents used in the treatment of PC. Moreover, it can block the enzymatic degradation of
multiple anti-cancer agents. WhatвЂ™s more,
blood level monitoring can be used to evaluate
absorption and hence the bioavailability of this
anti-cancer agent.
Because of these unique properties, HDK has
great potential for the therapy of prostate cancer.
However, the FDA has never approved the use of
HDK for the treatment of PC, and many physicians are unaware of the efficacy of HDK or are
afraid of its toxicity based on exaggerations of
HDKвЂ™s effect on the liver. Certainly, physicians
should consider the use of HDK for active therapy of PC and well-designed trials should be
undertaken and/or completed to provide a better understanding of the pharmacology of antineoplastic agents. вќЏ
References
1. Pont A, Graybill JR, Craven PC, et al: High-Dose ketoconazole therapy and
adrenal and testicular function in humans. Arch Intern Med
144(11):2150-3) Nov 1984
2. Eichenberger T, Trachtenberg J, Toor P, et al: Ketoconazole: a possible
direct cytotoxic effect on prostate carcinoma cells. J Urol 141:190-1,1989.
3. Trachtenberg J, Halpern N, Pont A: Ketoconazole: a novel and rapid treatment for advanced prostate cancer. J Urol 30 (1):152-3, Jul 1983
4. Pont A, et al: Long-term experience with high dose ketoconazole therapy
in patients with stage D2 prostatic carcinoma. J Urol 137:902-4,1987.
5. Muscato JJ, Ahmann TA, Johnson KM, et al: Optimal dosing of ketoconazole (Keto) and hydrocortisone (HC) leads to long responses in hormone
refractory prostate cancer. Proc Am Soc Clin Oncol 13:229, 1994 (abstract).
6. Small EJ, et al: Ketoconazole retains activity in advanced prostate cancer
patients with progression despite flutamide withdrawal. J Urol 157:1204-7,
1997.
7. Small EJ, et al: Simultaneous antiandrogen withdrawal and treatment
with ketoconazole and hydrocortisone in patients with вЂњadvanced"
prostate carcinoma. Cancer 80:1755-9, 1997.
8. Scholz M, Strum S, Mittleman P. High Dose Ketoconazole and hydrocortisone for hormone refractory prostate cancer (HRPC). Proc Amer Soc Clin
Oncol: 19:370: 2000
9. Trachtenberg J, Pont A. Ketoconazole therapy for advanced prostate cancer. Lancet. 25(8400):433-5, Aug 1984
10. Jubelirer SJ, Hogan T. High dose Ketoconazole for the treatment of hormone refractory metastatic prostate carcinoma: 16 cases and review of the
literature. J Urol 142(1):89-91, Jul 1989.
(continued on page 9)
PCRI Expands into Hawaii
For several years, the PCRI has had offices on both coasts of the United
States. Now the Institute has expanded overseas, opening an office on
the island of Maui in the Hawaiian Islands. Manning the Helpline there
is David Derris at 808-891-0209. David is well known to many attendees
of PCRI national conferences, as he and his life partner, Eti Fuchs, have
been invaluable volunteers at these conferences.
A retired orthodontist, David has become
well versed in prostate cancer since he,
himself, was diagnosed with the disease
in 1996. Faced with a shortage of
prostate cancer specialists in the islands,
he embarked on a program of selfempowerment, learnвЂњMy mission in ing all he could about
bringing PCRI PC by reading and
to Hawaii is to speaking with prostate
cancer survivors on the
deliver reliable
mainland, and talking
information so to such experts as
men can make Drs. Fernand Labrie,
truly informed Howard Scher, Stephen
Strum, and Mark
decisionsвЂќ Scholz. In contrast to
the gloomy predictions he had gotten
from physicians on the islands, these and
other mainland experts helped him steer
a course of treatment away from invasive
local therapies and eventually his diagnosis was changed from prostate cancer to
atypical adenomatus prostate hyperplasia. Today, he continues a healthy prostate
diet, supplements, exercise, and stress
reduction, apparently free from PC.
In the process of dealing with his
prostate cancer scare, David decided to
is published by:
Prostate Cancer Research Institute
5777 W. Century Blvd., Suite 800
Los Angeles, CA 90045
Websites: www.prostate-cancer.org
www.pcri.org
do what he could for other men in the
islands who were facing the threat of
prostate cancer without readily available,
reliable information. In 1997, he and two
other prostate cancer patients founded
the Maui chapter of US TOO!, and today
he is very active on the PC scene. When
asked how active, he replied:
вЂњI have been the prostate cancer chair
of the Maui ACS chapter, giving talks on
prostate health awareness and early
detection of PC. I have put on 1/2-day
prostate health symposiums and set up
free PSA and DRE testing events on the
Island. I have also traveled to the islands of
Molokai and Lanai to present prostate
education and explain early detection of
prostate cancer programs. When speaking with newly diagnosed men, I regularly suggest they have their biopsy slides reread by a prostate pathologist before
making any treatment decision. And, of
course, I continue my self-education
through such opportunities as the PCRI
conferences.
вЂњIn the islands we now have prostate
cancer patient support groups on Oahu
(Honolulu), the Big Island (Hawaii), Maui,
and Kauai. On the state and local levels,
the ACS chapters support the prostate
support groups and sponsor statewide PC
awareness and early detection programs.
But the ACS and US TOO! chapters are
just able to scratch the surface. We are still
trying to find ways to reach larger numbers of men and especially those ethnic
groups that are under-served by the
health services. There are no doctors that
I know of, anywhere in the islands, who
specialize in treating just prostate cancer
patients.
вЂњWithout reliable information to
guide them, men on the islands are too
likely to put off being tested for PC, and
when they are diagnosed with the disease, they may make critical treatment
decisions before they understand the biology and extent of their tumor. My mission
in bringing PCRI to Hawaii is to deliver reliable information so men can make truly
informed decisions and thus do away
with unnecessary pain and suffering
caused by either the under-treatment or
over-treatment of prostate cancer.вЂќ
And thatвЂ™s why the PCRI has expanded
into this westernmost U.S. state. вќЏ
NONPROFIT ORG.
U.S. POSTAGE
PAID
LIFE EXTENSION
FOUNDATION

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