text:
Risk stratification in the hormonal treatment of patients with prostate cancer.
ABSTRACT Prostate cancer (PCa) is the most common type of cancer found in American men, other than skin cancer. The American Cancer Society estimates that there will be 186,320 new cases of prostate cancer in the United States in 2008. About 28,660 men will die of this disease this year and PCa remains the second-leading cause of cancer death in men. One in six men will get PCa during his lifetime and one in 35 will die of the disease. Today, more than 2 million men in the United States who have had PCa are still alive. The death rate for PCa continues to decline, chiefly due to early detection and treatment, and improved salvage therapy such as hormone therapy (HT). HT continues to be a mainstay for primary-recurrent PCa and locally-advanced PCa. However, HT is associated with many undesirable side effects including sexual dysfunction, osteoporosis and hot flashes, all of which can lead to decreased quality of life (QOL). These risks are seen in both long- and short-term HT regimens. Additionally, research in recent years has revealed trends related to clinico pathological variables and their predictive ability in HT outcomes. Awareness of the potential adverse effects, the risks associated with HT and the prognostic ability of clinical and pathological variables is important in determining optimal therapy for individual patients. A rigorous evaluation of the current scientific literature associated with HT was conducted with the goal of identifying the most favorable balance of benefits and risks associated with HT.
- Citations (127)
- Cited In (0)
Article: Intermittent androgen deprivation for biologic recurrence after radical prostatectomy: long-term experience.[Show abstract] [Hide abstract]
ABSTRACT: To analyze the oncologic results of intermittent androgen deprivation (IAD) for biochemical recurrence after radical prostatectomy (RP). A total of 57 patients with biochemical recurrence after RP have been treated with IAD at our institution. The 57 patients were divided into two groups: group 1 comprised 29 patients who received salvage radiotherapy after RP; group 2 comprised 28 patients who did not receive salvage radiotherapy. Hormonal therapy during the first treatment phase consisted of an antiandrogen alone. This treatment was maintained for 3 months after the prostate-specific antigen (PSA) level had become undetectable and was then discontinued. Hormonal therapy was resumed when the PSA level exceeded 4 ng/mL; treatment was discontinued when the PSA level dropped to less than 1 ng/mL. The patients in group 1 had less favorable characteristics than those in group 2 in terms of pathologic stage and Gleason score. Overall, the median follow-up after starting hormonal therapy was 92 months (range 36 to 176). The percentage of each cycle that was spent "off" treatment decreased from 60% to 50%. During follow-up, 38.6% of patients required a luteinizing hormone-releasing hormone analog for nonresponse to the antiandrogen alone, and 15.8% experienced metastatic progression. The cancer-specific mortality rate was 12.3%; all patients who died of prostate cancer were from group 1. The median interval between initiation of hormonal therapy and cancer-related death was 86 months. In our experience, IAD for biochemical recurrence after RP provided satisfactory long-term oncologic results. Our data suggest that IAD can be initiated with an antiandrogen alone.Urology 05/2005; 65(4):724-9. · 2.42 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Prostate cancer is a leading cause of cancer death in men. Treatment goals for men with advanced prostate cancer include prolonging survival, preventing or delaying symptoms due to disease progression, improving and maintaining quality of life, reducing treatment related morbidity. Androgen suppression therapy is considered a mainstay of treatment for men with advanced prostate cancer. However it is not clear whether early androgen suppression for men with locally advanced disease or asymptomatic metastases improves length and quality of life compared to androgen suppression deferred until signs and symptoms of clinical progression. This systematic review assessed the efficacy and adverse effects of primary therapy with early versus deferred androgen suppression therapy in men with advanced prostate cancer. Randomized controlled trials were searched in general and specialized databases (MEDLINE, EMBASE, CancerLIT, Cochrane Library, VA Cochrane Prostate Disease register) and by reviewing bibliographies including those of the Blue Cross and Blue Shield Association Technology Evaluation Center/Evidence-based Practice Center of the Agency for Healthcare Research and Quality (BCBS/TEC-AHRQ) report No.4. All published randomized trials were eligible for inclusion provided they: randomized men with advanced prostate cancer to early versus deferred androgen suppression; reported overall, progression-free, and cancer-specific survival, and/or adverse events; did not utilize androgen suppression as adjuvant therapy to radiation treatment. An independent reviewer using a standardized form extracted information on trial characteristics, interventions, and outcomes. Results were reviewed for accuracy and discrepancies resolved by discussion. The main outcome measure for comparing effectiveness was the overall survival at 1, 2, 5 and 10 years. Progression-free survival, cancer-specific survival, complications due to disease progression and the incidence of adverse effects of treatment were also measured. Four trials involving 2,167 patients were included in this review. All of the trials were conducted prior to use of prostate specific antigen (PSA) testing. There was variability between studies regarding the treatments used and the requirements for initiation of treatments. The percent overall survival at 1, 2, 5, and 10 years for the early treatment group was 88%, 73%, 44%, and 18%. For the deferred therapy group the percent overall survival was 86%, 71%, 37%, and 12%. The pooled estimate for the difference in overall survival favored early therapy but was significant only at 10 years when few patients had survived [OR = 1.16 (95% CI: 0.90 to 1.49) at 1 year, 1.08 (95% CI: 0.89 to 1.33) at 2 years, 1.19 (95% CI: 0.95 to 1.50) at 5 years, and 1.50 (95% CI: 1.04 to 2.16) at 10 years]. The pooled estimate of prostate cancer specific survival at 2, 5, and 10 years favored early therapy though the confidence intervals were wide and the results not statistically different. The risk differences at 2, 5, and 10 years were 2.7%, 5.8%, and 4.6%. Although each study used unique definitions of progression free survival, all studies found progression free survival was consistently better in the early intervention group at all time points. Complications due to disease progression were only reported in one study but were more frequent in the deferred treatment group. Adverse events due to treatment were also only reported in one study but occurred more frequently in the early treatment group. The evidence from randomized controlled trials is limited by the variability in study design, stage of cancer and subjects enrolled, interventions utilized, definitions and reporting of outcomes and the lack of PSA testing for diagnostic and monitoring purposes. However, the available information suggests that early androgen suppression for treatment of advanced prostate cancer reduces disease progression and complications due to progression. Early androgen suppression may provide a small but statistically significant improvement in overall survival at 10 years. There was no statistically significant difference in prostate cancer specific survival but a clinically important difference could not be excluded. These outcomes need to be evaluated with the evidence suggesting higher costs and more frequent treatment related adverse effects with early therapy. Additional studies are required to evaluate more definitively the efficacy and adverse effects of early versus delayed androgen suppression in men with prostate cancer. In particular trials should evaluate patients with advanced prostate cancer diagnosed by PSA testing and men with persistent or rising PSA levels following treatment options (e.g. radical prostatectomy, radiation therapy or observation) for clinically localized disease.Cochrane database of systematic reviews (Online) 02/2002; · 5.70 Impact Factor
Article: Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy.[Show abstract] [Hide abstract]
ABSTRACT: We characterize the consequences of androgen deprivation therapy on body composition in elderly men. Using a dual energy x-ray absorptiometry instrument, we determined the changes in bone mineral density, bone mineral content, fat body mass and lean body mass in 35 patients with prostate cancer without bone metastases who received luteinizing hormone releasing hormone analogue for 12 months. At baseline conditions 46% of cases were classified as osteopenic and 14% as osteoporotic at the lumbar spine and 40% were osteopenic and 4% osteoporotic at the hip. Androgen deprivation significantly decreased bone mineral density either at the lumbar spine (mean gm./cm.2 [SD] 1.00 [0.194], 0.986 [0.172] and 0.977 [0.182] at baseline, and 6 and 12 months, respectively, p <0.002) or the hip (0.929 [0.136], 0.926 [0.144] and 0.923 [0.138], p <0.03). A more than 2% decrease in bone mineral density was found at the lumbar spine in 19 men (54.3%) and at the hip in 15 (42.9%). Bone mineral content paralleled the bone mineral density pattern. Lean body mass decreased (mean gm. [SD] 50,287 [6,656], 49,296 [6,554] and 49,327 [6,345], p <0.003), whereas fat body mass consistently increased (18,115 [6,209], 20,724 [6,029] and 21,604 [5,923] p <0.001). Serial bone densitometry evaluation during androgen deprivation therapy may allow the detection of patients with prostate cancer at risk for osteoporotic fractures, that is those with osteopenia or osteoporosis at baseline and fast bone loss. The change in body composition may predispose patients to accidental falls, thus increasing the risk of bone fracture.The Journal of Urology 06/2002; 167(6):2361-7; discussion 2367. · 3.75 Impact Factor
Page 1
Risk stratification in the hormonal treatment
of patients with prostate cancer
Matthew A. Uhlman, Judd W. Moul, Ping Tang, Danielle A. Stackhouse and Leon Sun
Abstract: Prostate cancer (PCa) is the most common type of cancer found in American men,
other than skin cancer. The American Cancer Society estimates that there will be 186,320 new
cases of prostate cancer in the United States in 2008. About 28,660 men will die of this disease
this year and PCa remains the second-leading cause of cancer death in men. One in six men
will get PCa during his lifetime and one in 35 will die of the disease. Today, more than 2 million
men in the United States who have had PCa are still alive. The death rate for PCa continues to
decline, chiefly due to early detection and treatment, and improved salvage therapy such as
hormone therapy (HT). HT continues to be a mainstay for primary-recurrent PCa and locally-
advanced PCa. However, HT is associated with many undesirable side effects including sexual
dysfunction, osteoporosis and hot flashes, all of which can lead to decreased quality of life
(QOL). These risks are seen in both long- and short-term HT regimens. Additionally, research
in recent years has revealed trends related to clinico pathological variables and their predictive
ability in HT outcomes. Awareness of the potential adverse effects, the risks associated with HT
and the prognostic ability of clinical and pathological variables is important in determining
optimal therapy for individual patients. A rigorous evaluation of the current scientific literature
associated with HT was conducted with the goal of identifying the most favorable balance of
benefits and risks associated with HT.
Keywords: prostate cancer, recurrence, survival, hormonal therapy, toxicity, risk factors,
quality of life
Risks and benefits of hormonal therapy
Since Huggins and Hodges discovered that
prostate cancer (PCa) cell growth is androgen
dependent, hormonal therapy (HT) has been
increasingly utilized for the treatment of PCa
[Huggins and Hodges, 1972; Huggins, 1967;
Huggins and Hodges, 1941]. Approximately
30% of the existing 2 million PCa patients receive
HT in the context of adjuvant/neo-adjuvant ther-
apy before or after radical prostatectomy (RP) or
external radiotherapy (XRT) [Smith, 2007]. HT
has become an increasingly common treatment
for organ-confined PCa in the United States
over thelast decade
Cooperberg et al. 2003]. With this increase in
popularity, patients are now receiving HT for
extended periods of time. HT is not without
risk, however, and is associated with numerous
side effects including vasomotor flushing, loss of
libido, erectile dysfunction, cognitive decline,
et al.
arterial stiffness, anemia, fatigue, gynecomastia,
mastodynia, osteoporosis leading to fractures,
obesity, sarcopenia, and cardiovascular disease
[Isbarn et al. 2008; Michaelson et al. 2008;
Higano, 2003]. More recently, metabolic compli-
cations including insulin resistance, diabetes,
dyslipidemia andmetabolic
been observed in patients receiving HT. These
findings have led some to suggest they are poten-
tial explanations for the increased cardiovascular
mortality seen in this population [Hakimian et al.
2008; Saigal et al. 2007; Tsai et al. 2007;
et al.
Yannucci et al. 2006], though some studies
have found no increase in cardiovascular mortal-
ity for men on androgen deprivation therapy
(ADT) [Efstathiou et al. 2009]. Given the large
side-effect profile of HT, it is understandable that
HT is associated with decreased quality of life
(QOL) [Fowler et al. 2002].
et al.
http://tam.sagepub.com 79
Therapeutic Advances in Medical OncologyReview
Ther Adv Med Oncol
(2009) 1(2) 79?94
! The Author(s), 2009.
Reprints and permissions:
Correspondence to:
Judd W. Moul, MD
Professor and Chief,
Division of Urologic
Surgery and Duke
Prostate Center, Duke
University Medical Center,
PO Box 3707, Durham,
Matthew A. Uhlman
Ping Tang
Danielle A. Stackhouse
Leon Sun
Division of Urologic
Surgery and Duke
Prostate Center,
Department of Surgery,
Duke University Medical
Center, Durham, NC 27710
Page 2
Prostate-specific antigen (PSA) recurrence
Patients with biochemical recurrence or PSA
recurrence (PSAR), an increase in PSA to greater
than 0.2ng/ml following curative therapy, con-
tinue to be the main subjects utilizing HT as it
has not been shown to be superior to current
treatments as a primary therapy for PCa [Akaza
et al. 2006]. Curative treatments such as radical
prostatectomy (RP) are effective for clinically-
localized PCa, however, up to 40% of men will
have biochemical evidence of cancer progression,
evident as a detectable serum PSA level within
10 years following initial treatment [Amling
et al. 2000; Pound et al. 1999; Catalona and
Smith, 1994; Zincke et al. 1994]. As a result, it
is important to be familiar with the key risk fac-
tors for PSAR following curative treatment. Risk
factors include age, race, clinical and pathological
stage, Gleason score (GS), PSA and small pros-
tate size [Khatami et al. 2007; Freedland et al.
2005; Moul et al. 2001].
With the growing number of patients on HT
and limited data available on optimal treatment
regimens, it is important to consider the risks
and benefits associated with each therapeutic
option. This article focuses on the risks and
strategies for stratifying patients in order to
achieve maximal benefits while effectively balan-
cing risks.
HT, aswell as
Methods of HT
Castration remains the gold standard of HT.
It is accomplished in one of two ways that have
been shown to be equally effective ? medical and
surgicalcastration [Seidenfeld
Vogelzang et al. 1995; Kaisary et al. 1991].
Medical castration is accomplished through the
administration of a luteinizing hormone-releasing
blockade (CAB, castration+anti-androgen) or
triple androgen blockade (CAB+5a-reductase
inhibitor). Other pharmacological options are
available, but rarely utilized due to unacceptable
clinical side effects [The Veterans Administration
Co-Operative Urological Research Group, 1967]
or decreased efficacy. Surgical castration on the
other hand is accomplished through bilateral
orchiectomy. Both medical and surgical castra-
tion achieve similar therapeutic goals, although
they do so in different ways and, consequently,
have different associated risks and benefits.
et al.
Medical castration
LHRH agonists
Since the introduction of LHRH agonists in the
early 1980s, their use in the treatment of PCa
has continued to increase. LHRH agonists work
primarily through reducing active levels of andro-
gens. Currently available LHRH agonists include
leuprorelin, goserelin, triptorelin, and buserelin.
More recently, sustained-release formulations
that require dosing every 1?12 months have
become available. Today, LHRH agonists are
the most common form of HT [Boccon-Gibod,
2005] and the most extensively studied.
Nonsteroidal anti-androgens are another popular
form of HT, in large part due to the decreased
sexual side effects as compared to LHRH agonists
or orchiectomy [Dreicer, 2000]. Anti-androgens
work by blocking androgen receptors, which
keeps circulating androgen levels normal or
increased. Currently available agents include fluta-
mide, nilutamide and bicalutamide. With the lack
of randomized controlled trials, limited recom-
mendations for anti-androgen monotherapy exist.
Combined androgen blockade and triple
androgen blockade
Combined androgen blockage (CAB) is a combi-
nation therapy which includes medical or surgical
castration combined with an anti-androgen. It is
also referred to as maximal androgen blockade
CAB has been investigated in many different trials,
but withconflicting results. In1989, Crawfordand
colleagues with a cohort of 603 men with dissemi-
nated, untreated PCa, showed a 25% survival
advantage (35.6 vs 28.3 months) in those receiving
leuprolide with flutamide (CAB) versus those
receiving leuprolide plus placebo [Crawford et al.
1989]. A decade later however, Eisenberger and
colleagues found no difference in survival in 1387
men with metastatic PCa who were treated with
1998]. More recently, a meta-analysis of 30 trials
showed that, at 5 years, treatment with CAB
versus castration was associated with a small, clin-
ically insignificant survival advantage of 2?3%
when compared to castration alone [Prostate
Cancer Trialists' Collaborative Group, 2000].
These findings were confirmed in 2006 in a
systematic review by Lukka et al. [Lukka et al.
2006]. Both studies questioned the benefit of
et al.
Therapeutic Advances in Medical Oncology 1 (2)
Page 3
CAB given the increased side effects and potential
decreased QOL associated with treatment. A
recent review found more support for CAB, pri-
marily due to a potential for more effective andro-
gen blockade with bicalutamide [Klotz, 2008].
Currently, monotherapy through orchiectomy or
LHRHagonist, rather thanCABis recommended
for the treatment of men with recurrent PCa.
Triple androgen blockage (TAB) is CAB with the
addition of a 5a-reductase inhibitor. TAB has
been studied far less than CAB. Initial results
from Leibowitz and Tucker in 2001 showed
TAB with finasteride maintenance to be promis-
ing [Leibowitz and Tucker, 2001]. However,
little data has been published since with no
trials supporting its use over the currently avail-
able therapies.
Pure LHRH antagonists
LHRH antagonists are one of the newer forms of
HTand work by blocking LHRH receptors. The
major advantage of these drugs is the absence of
biochemical flare, a transient increase in testos-
terone associated with the initiation of androgen
deprivation therapy (ADT). Abarelix, the first
LHRH antagonist, was as effective as leuprolide
at suppressing testosterone, but was taken off the
market due to an increased rate of immediate-
onset systemic allergic reactions [Trachtenberg
et al. 2002; Mcleod et al. 2001; Tomera et al.
2001]. More recently, degarelix has been intro-
duced and has not been associated with allergic
reactions [Klotz et al. 2008]. To date there have
been no long-term trials examining the efficacy of
LHRH antagonists versus the currently available
Surgical castration
Bilateral orchiectomy as a treatment for advanced
PCa was first investigated by Huggins and
Hodges in a study of 21 patients with metastatic
PCa. Of those treated, 15 had either subjective or
objective improvement of pain or neurologic
symptoms [Huggins
Orchiectomy is a relatively simple, minimally-
invasive procedure that is easy to perform
[Loblaw et al. 2007]. It remains the most popu-
lar HT method in developing countries [Deng
et al. 2004]. However, with the advent of viable
medical alternatives, and because of the physical
and psychological discomforts and irreversibility
of orchiectomy, surgical castration has fallen out
of favor in developed countries [Mcleod, 2003;
Clark et al. 2001].
and Hodges,1941].
The role of hormone therapy in prostate
Hormone therapy as a primary therapy for
localized prostate cancer
There is currently no evidence supporting the use
of HT in patients with localized PCa. Iversen and
colleagues in a randomized controlled trial with
1,218 patients showed that treatment with
150mg/day of bicalutamide in men with early,
nonmetastatic PCa did not significantly improve
survival. In fact, a trend toward decreased overall
survival was seen in the group receiving bicaluta-
et al.
Urological Association (AUA) guidelines state
that primary ADT may be employed with the
goal of providing symptomatic control of PCa
for patients in whom definitive treatment with
surgery or radiation is neither possible nor accep-
table. Today, neither the AUA or the European
Association of Urology (EAU) recommends the
use of HTas primary therapy for PCa in patients
with localized disease who are candidates for
Thompson et al. 2007].
The American
et al.
Hormone therapy as a primary therapy for
locally advanced or metastatic disease
For patients with metastatic disease, HT has
been shown to provide quality-of-life improve-
ments including reduction in fractures, bone
pain and ureteral obstruction [Huggins et al.
1941; Huggins, 1967]. A systematic review and
meta-analysis of 24 single-therapy HT trials for
men with advanced PCa showed no difference in
survival between LHRH agonist and orchiectomy
groups, though data showed a trend toward
decreased survival in patients treated with anti-
androgens [Seidenfeld et al. 2000]. This finding
was confirmed by Tyrell and colleagues in a pro-
spective trial including 1,453 men with locally-
advanced or metastatic PCa. Treatment with
bicalutamide versus castration was found to be
less effective for patients with metastatic disease.
No survival difference was seen for patients with
locally-advanced disease [Tyrrell et al. 1998].
The authors did point out the significant
decrease in sexual side effects in patients treated
with bicalutamide and that it could be used in
patients for whom surgical and medical castra-
tion is not indicated or acceptable. Wirth and
associates recently reported 7-year results from
the Early Prostate Cancer program which rando-
mized men to standard of care (RP, radiation or
watchful waiting) +/? bicalutamide. At 7 years,
MA Uhlman, JW Moul et al.
Page 4
men with locally-advanced disease receiving
bicalutamide, showed a 34% reduction in pro-
gression-free survival, but no difference in overall
survival [Wirth et al. 2007]. CAB has also been
explored in patients with metastatic disease. In
the largest trial to date, Eisenberger and collea-
gues found no difference in survival in 1,387 men
with metastatic PCa who were treated with
castration +/? flutamide [Eisenberger et al. 1998].
A number of other studies have examined the
efficacy of HT in patients with locally-advanced
or metastatic disease that looked at immediate
versus delayed treatment delivery. These studies
are discussed below. The AUA and EAU cur-
rently recommend treating patients with asymp-
tomatic metastatic PCa with HT, however, the
optimal time to initiate treatment is unknown.
For patients with symptomatic metastatic PCa,
HT should be initiated immediately.
Hormone therapy combined with radical
Neo-adjuvant therapy with prostatectomy. There
is little evidence to suggest that neo-adjuvant
LHRH agonists with RP are of any survival
benefit. Boorjian and associates showed, in a ret-
rospective trial of 507 men, 455 of which were
treated with HT, that adjuvant HT decreased the
risk of PSAR and local recurrence, but did not
significantly affect overall survival [Boorjian et al.
2007]. Recently a large Cochrane meta-analysis
demonstrated that neo-adjuvant HT (LHRH
agonists and anti-androgens) can significantly
improveadverse pathological
including positive margins, and tumor stage,
but does not improve overall survival [Kumar
et al. 2006]. Currently, neo-adjuvant HT with
RP is not recommended by the AUA or EAU.
Adjuvant therapy with prostatectomy. A number
of trials have shown that adjuvant HT following
prostatectomy does not increase survival as com-
pared to prostatectomy alone. In one of the lar-
gest trials to date ? the Early Prostate Cancer
program ? Wirth and colleagues showed that
patients receiving adjuvant bicalutamide had no
advantage in survival over those receiving pla-
cebo [Wirth et al. 2007]. In another retrospective
trial by Siddiqui and colleagues, ADT following
RP was associated with increased progression-
free survivalandcancer-specific
However, it was not found to increase overall sur-
vival [Siddiqui et al. 2008]. Finally, for patients
associates found that ADT was associated with
a significantly reduced risk of PSAR and local
recurrence, but did not demonstrate a survival
advantage [Boorjian et al. 2007].
lymph-nodemetastases,Boorjian and
The only circumstance in which adjuvant HT
with RP has been shown to increase survival
was in a small study of 98 men with lymph-
node metastases. The study assigned patients to
immediate or delayed ADT and after nearly
12 years of follow up, found that those who
receivedimmediate HT
increased overall survival [Messing et al. 2006].
The study has been criticized though due to its
small size and lack of generalizability to the pop-
ulation at large.
had significantly
Currently, there is no evidence to suggest that
neoadjuvant or adjuvant HT with RP provides
any overall survival benefit in patients without
lymph-node metastases and as such, neither
neo-adjuvant nor adjuvant HT with RP is cur-
rently recommended by the AUA or EAU. For
patients with lymph-node positivity, the EAU
recommends immediate ADT whereas the AUA
does not address the situation in their guidelines.
Hormone therapy combined with radiation
Neoadjuvant radiotherapy. ADT with radiother-
apy has been shown to significantly increase over-
all survival in a number of studies. Bolla, in a
randomized trial with a cohort of 415 men with
locally-advanced PCa, showed that the addition
of an LHRH agonist (goserelin) to radiotherapy
significantly improved overall survival at 5 years
(78 versus 62% with radiotherapy alone) [Bolla,
1997]. Pilepich and colleagues also found that
the addition of an LHRH agonist to radiotherapy
rates at 10 years in men with locally-advanced
disease (16 versus 22%) [Pilepich et al. 2005].
Of particular interest was the finding that
improved survival appeared preferentially in
patients with a GS of ?7. Additionally, Iversen
and colleagues showed that 150mg/day of bica-
lutamide in addition to radiation therapy reduced
the risk of death by 35% in men with locally-
shown a survival advantage in men receiving
neoadjuvant- or adjuvant-combined androgen
blockade (LHRH agonist+anti-androgen) with
studies have
Therapeutic Advances in Medical Oncology 1 (2)
Page 5
Another study by D'amico and colleagues also
demonstrated a survival advantage in men receiv-
ing adjuvant HT (LHRH agonist+anti-andro-
gen) with radiotherapy [D'amico et al. 2004].
Additional studies have shown neoadjuvant HT
with radiotherapy significantly increases overall
survival [Denham et al. 2005; Laverdiere et al.
2004]. Currently, both the AUA and EAU recom-
mend neo-adjuvant and adjuvant HT for patients
with high-grade or locally-advanced PCa who
will be receiving radiotherapy [Heidenreich et al.
2008; Thompson et al. 2007].
Hormone therapy combined with other
treatment modalities for prostate cancer
HT is often given to patients before treatments
such as brachytherapy to reduce the size of the
prostate [Lee, 2002]. However, a number of stu-
dies have shown that neo-adjuvant ADT with
brachytherapy does not lead to increased survival
[Merrick et al. 2007; Machtens et al. 2006;
Galalae et al. 2004]. One retrospective study
found that men receiving neo-adjuvant ADT
with brachytherapy had significantly reduced
survival, but due to the nature of the study, the
findings must be interpreted lightly [Beyer et al.
2005]. Currently, neither the AUA nor the
EAU guidelines recommend the use of neo-
adjuvant HT with brachytherapy.
Hormone therapy following PSA recurrence
Patients with PSAR continue to be the most
common recipients of HT [Akaza et al. 2006].
However, there is little evidence guiding these
androgen-deprivation therapy reduces metastatic
complications including ureteral obstruction,
bone pain and fractures [The Medical Research
CouncilProstate Cancer
Research Group, 1967]. Although there has
never been a survival advantage demonstrated
with HT, it can provide significantly increased
QOL topatientswith
However, the majority of patients receiving HT
do not have metastatic disease. HT is associated
with significant side effects that can affect QOL
negatively and, as a result, physicians are faced
with questions of when to initiate treatment and
on what schedule to continue it.
1997; Veterans
Immediate versus delayed therapy. For locally-
advanced and metastatic PCa, there is much
debate about the best time to start therapy.
Immediate or early therapy refers to the initiation
of HT as soon as a patient's PSA begins to rise
following surgery, whereas delayed therapy gen-
erally begins when clinical signs of metastatic dis-
ease are present. Only a few randomized trials for
immediate versus delayed therapy exist today.
The Medical Research Council, with a cohort
of 983 men with locally-advanced or metastatic
PCa, randomized men to immediate or delayed
HT and found no survival difference between
therapies. Patients receiving immediate therapy,
however, did have significantly lower rates of
pathological fractures, bone pain and ureteral
obstruction [The Medical Research Council
Prostate Cancer Working Party Investigators
Group, 1997]. More recently, Moul and collea-
gues with the largest retrospective cohort to date
with 1,352 patients, found that immediate ther-
apy was associated with delayed clinical metasta-
ses in patients with a GS >7 or a PSA doubling
time <12 months. No survival advantage was
seen. A Cochrane review by Nair and colleagues
concluded that immediate HT is associated with
a small, but significant survival advantage at 10
years [Nair et al. 2002]. However, it also con-
cluded that early therapy is associated with
increased costs and more side-effects. Finally, a
review by Messing and colleagues concluded that
immediate HT may have a survival advantage for
men with non-metastatic, lymph node positive
disease [Messing et al. 2006]. Men with meta-
static disease may not see a survival advantage,
but will see improved QOL with HT.
patients are undergoing HT for increasingly
longer periods of time, providers are now faced
with the challenge of how often to administer
HT. Nearly all patients who undergo HT will
eventually develop PCa that is resistant to ther-
apy. This is termed castration-resistant PCa
(CRPC) and currently there is little that physi-
cians can do to treat the disease. A number of
trials have been conducted comparing intermit-
tent HT (IHT) with continuous HT (CHT).
A number of trials in the past have concluded
that IHT is no worse than CHT, but due to
small sizes of the trials in question, limited
recommendations have been made [Prapotnich
et al. 2009; Peyromaure et al. 2005; De La
Taille et al. 2003; Youssef et al. 2003]. A
Cochrane review completed in 2007 found that
there is not enough data to suggest that IHT is
more effective than CHT for survival or disease
progression and limited information suggests that
intermittenttherapy. As
MA Uhlman, JW Moul et al.
http://tam.sagepub.com 83
Page 6
IHT may have slightly reduced adverse events
[Conti et al. 2007]. A recently completed rando-
mized trial by Calais Da Silva that included 626
men with locally-advanced or metastatic disease
found that men receiving IHT versus CHT were
not significantly different with respect to survival.
The IHT group had more cancer deaths, but less
cardiovascular deaths. QOL was no different
while undergoing treatment, though men on
IHT had significantly better sexual activity and
the overall cost was significantly reduced in the
IHT group.
Currently the AUA does not have definitive
recommendations regarding treatment initia-
tion-time or treatment intervals for HT following
PSAR. The EAU guidelines suggest that a period
of watchful waiting may be appropriate with a
possibility of HT at a later time. They also state
that lymph node-positive disease may be an indi-
cation for immediate HT, but they do not go so
far as to recommend it. For intermittent versus
continuous therapy, the EAU guidelines state
that IHT may be acceptable for some patients,
but that randomized trials are needed.
Risks associated with hormone therapy
HT continues to be a popular treatment option
for men with recurrent or advanced PCa, how-
ever, the treatment is not without risks. Medical
and surgical castration have been shown to be
equally effective treatments for PCa [Vogelzang
et al. 1995; Kaisary et al. 1991], but today, for
multiple reasons, medical options are more often
utilized. However, regardless of therapy choice,
both forms of treatment have significant side
effects. LHRH agonists and surgical castration
both effectively reduce testosterone levels and as
a result have a similar side-effect profile, though
there have been limited reports on orchiectomy
alone. In addition there is limited data on anti-
androgens,which makes
between treatments difficult. Even with limited
data on these specific therapies, a great amount
of research has been conducted looking at LHRH
agonists and anti-androgens.
Biochemical flare
A side effect specific to LHRH agonists is the flare
phenomenon. Beforethe'resetting'oftheanterior
hypothalamic-pituitary-gonadal axis, stimulation
of the anterior pituitary with a LHRH agonist
results in a surge of increased testosterone. The
flare reaction is not seen in patients treated with
other formsof castration. Thompson and
associates demonstrated, in a review of 765
patients from 9 studies, that 10.9% of patients
experienced a flare and 2% died [Thompson
et al. 1990]. In patients with overt metastases
who are at risk ofdevelopingsymptoms associated
with a surge in testosterone with initial LHRH
agonist administration, anti-androgen therapy
should precede or be co-administrated with the
LHRH agonist and be continued in combination
for at least 7 days [Schulze and Senge, 1990;
Labrie et al. 1987]. An exception exists for
patients at high risk of impending spinal cord
compression, for whom surgical castration is
recommended [Heidenreich et al. 2008].
Sexual side effects
Sexual side effects are the most common among
patients undergoing HT.
research has demonstrated differences in side-
effect rates between HT with LHRH agonists
and anti-androgens.
ADT. The side effects of LHRH agonists are
comparable with those of castration, principally
due to the reduction in testosterone levels to
<50ng/dl achieved by both therapies.
The list of side effects with HT is significant and
patient considerations on QOL must be factored
into any treatment decisions. Sexual side effects
are reported at variables, but nonetheless there
are high rates with castration. Decreased libido
is reported in up to 90% of patients and erectile
dysfunction levels vary among studies ranging
between 15?72% [Diblasio et al. 2008; Potosky
et al. 2001]. In one study, Potosky and collea-
gues reported that sexual function among a
cohort of 431 men was impaired similarly in
patients undergoing either surgical or medical
castration. In the study, 63.6 and 58.0% of
patients (surgical and medical castration respec-
tively) reported 'no interest' in sexual activity fol-
lowing HT, up from 27.6 and 31.7% before
treatment [Potosky et al. 2001].
Diblasio, with a cohort of 359 patients, found an
erectile-dysfunction rate of only 14% of patients
following HT, but did admit that under-reporting
likely played a role in the number [Diblasio et al.
2008]. Fowler and colleagues, with a cohort of
over 1,300 men who underwent radical prosta-
tectomy with or without HT, found that men
receiving HT were significantly more likely
to have decreased libido (69 versus 29% had
'no sex drive within the last 30 days') and were
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84 http://tam.sagepub.com
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significantly more likely to have had no erections
since surgery (72 versus 55%) [Fowler et al.
Anti-androgens. Despite conflicting studies, the
number of men receiving oral anti-androgen ther-
apy alone has grown, in part due to the presumed
decrease in sexual side effects associated with
therapy. One study by Iversen and colleagues
much more likely to maintain sexual interest
men receiving
[Iversen et al. 1998]. See and Tyrrell found that
patients given bicalutamide at a dose of 150mg/
day before radiotherapy had rates of impotence
(12.7%) and decreased libido (4%) that were not
statistically different from men receiving placebo.
These results are much lower than reported rates
for men undergoing more traditional ADT [See
and Tyrrell, 2006].
Osteoporosis and fractures
As patients continue to receive HT for longer
periods of time, osteoporosis has emerged as a
significant risk of treatment.
ADT. ADT has been shown to increase the risk of
osteoporosis and pathological fractures in multi-
ple studies [Malcolm et al. 2007; Smith et al.
2006a; Shahinian et al. 2005; Preston et al.
2002]. Longer-term treatment
increased age (>70) at treatment initiation and
CHT have all been shown to increase rates of
2007]. Reported rates of osteoporosis vary
widely within the literature, with a range of
7?23% [Malcolm et al. 2007; Shahinian et al.
2005]. Rates of fractures in patients on ADT
also vary widely between studies, with a range
of approximately 5?20% with fracture rates for
control patientsgenerally
0.7?12% [Malcolm et al. 2007; Smith et al.
2006a; Lopez et al. 2005; Shahinian et al.
2005; Oefelein et al. 2001; Hatano et al. 2000;
Townsend et al. 1997]. Lopez and colleagues
found a four-fold increase in fracture risk in
patients on CAB [Lopez et al. 2005]. Shahinian
and associates looking at a cohort of more than
50,000 men, found ADT was associated with a
significant increase in osteoporosis (0.59?6.92%
versus 0.46?3.59% for non-ADT patients) and
fractures (3.41?19.37%
[Shahinian et al. 2005].
with ADT,
et al.
inthe rangeof
A number of trials have shown that the adminis-
tration of bisphosphonates during ADT can
increase bone-mineral density (BMD). Yuen and
colleagues in a review of 1,955 patients found
bisphosphonate administration led to significant
decreases in pain and skeletal events (fractures,
spinal cord compression and bone surgery)
[Yuen et al. 2006]. Others have demonstrated
that taking pamidronate during HT reduces
bone loss in the hip and lumbar spine [Diamond
et al. 2001; Smith et al. 2001]. Perhaps the most
important agent for overall skeletal health for men
with PCa, with metastases or undergoing HT, is
zoledronic acid. It has been shown to prevent
bone loss in patients with locally-advanced PCa
receiving HT [Polascik and Mouraviev, 2008;
Ryan et al. 2006]. In addition, zoledronic acid
has been shown to reduce the number of
skeletal-related events (SRE) in men with CRPC
[Polascik et al. 2005; Saad et al. 2004; 2002].
Anti-androgens. Anti-androgen therapy, unlike
ADT, has not been shown to increase the risk of
osteoporosis. A number of smaller trials have
demonstrated reduced rates of osteoporosis with
anti-androgen use versus ADT [Sieber et al. 2004;
Smith et al. 2004; Tyrrell et al. 2003]. Wadhwa
and colleagues in a prospective trial of 618 men
randomized to LHRH agonist or anti-androgen,
showed that men on anti-androgen, therapy main-
tained BMD whereas those taking a LHRH ago-
nist had a significant loss. The exact mechanism
through which anti-androgens may decrease the
risk of osteoporosis in unknown, however, it is
known that the drugs effectively block the effects
of testosterone while allowing serum testosterone
levels to remain normal or elevated. It has been
suggested that the increased testosterone levels,
through peripheral aromatization, may lead to
higher levels of estrogen which in turn may slow
the rate of bone loss [Verhelst et al. 1994].
Randomized trials are needed to confirm the
effects of anti-androgens on osteoporosis, however
preliminary findings are encouraging.
Metabolic issues
ADT is associated with significant body composi-
tion/metabolic changes including increased rates
of metabolic syndrome, diabetes, hypercholester-
olemia, hypertriglyceridemia, and coronary artery
disease (CAD) [Kintzel et al. 2008; Braga-Basaria
et al. 2006a, 2006b]. Increased body fat and
reduced lean-muscle mass are well-known effects
of ADT [Van Londen et al. 2008; Smith, 2004;
Berruti et al. 2002; Chen et al. 2002] with fat
MA Uhlman, JW Moul et al.
http://tam.sagepub.com 85
Page 8
content increasing up to 20% in one study and
lean body mass decreasing by 3.8%. Often these
changes are evident in the first 3?6 months of
ADT [Smith et al. 2006b; Berruti et al. 2002].
Keating and colleagues showed that ADT was
(Hazard ratio (HR)¼1.44 for LHRH agonist
and 1.34 for orchiectomy), but interestingly
found that only treatment with a LHRH agonist,
andnot orchiectomy,
increased risk for CAD, MI and sudden cardiac
death [Keating et al. 2006]. Saigal and colleagues
found that men receiving ADT for at least 1 year
were at a 20% higher risk of serious cardiovascular
morbidity than men not receiving ADT. They also
found that risk began within 12 months of treat-
ment initiation. Anti-androgen therapy has not
been associated with significant metabolic side
effects [Saigal et al. 2007].
levels ofdiabetes
was associatedwith
Cognitive issues
As HT duration has increased, cognitive decline
has become a more discussed potential side
effect. Within the last decade a large number of
studies havedemonstrated
between HTand subtle, but significant cognitive
changes. A review performed by Nelson and
associates showed the three cognitive areas that
were affected most often by ADT were visuospa-
tial abilities, working memory and executive
functioning [Nelson et al. 2008]. To our knowl-
edge, no large studies have examined anti-
androgen therapy and cognitive decline.
the relationship
Additional side effects
Gynecomastia and breast tenderness are the most
commonly reported side effects of oral anti-
androgen therapy alone with rates as high as
67.1 and 75.1%, respectively. ADT is generally
associated with significantly lower rates with
reports of gynecomastia and breast tenderness
as low as 3.8 and 1.9% respectively [Iversen
et al. 1998]. Potosky and colleagues reported
gynecomastia rates of 24.9 and 9.7% for patients
on LHRH agonists and receiving orchiectomy
respectively [Potosky et al. 2001].
Hot flashes are another unpleasant, but common
side effect of ADT with incidence rates ranging
from 50–80% [Sharifi et al. 2005; Holzbeierlein
et al. 2004; Higano, 2003; Chen et al. 2002;
Potosky et al. 2001]. Up to 30% of men on
ADT report hot flashes as the most debilitating
side effect of therapy [Sharifi et al. 2005;
Holzbeierlein et al. 2004; Chen et al. 2002].
Rates of hot flashes for medical and surgical
castration patients are similar with some reports
suggesting a slightly, but not statistically signifi-
cant, reduced incidence
2001; Sarosdy et al. 1999; Parmar et al. 1987].
Hot flashes are reported at much lower rates
(10?15%) withanti-androgen
et al. 2006; Iversen et al. 1998].
et al.
Risk Stratification for hormone therapy
For many years, patients with PSAR have effec-
tively fallen into their own category making further
treatment stratification difficult. This is in large
part due to a lack of randomized trials and the
resultant dearth of prognostic data for patients
who have initiated HT. As a result, knowing the
optimal balance of risks and rewards is compli-
cated. Some trials however have reported prognos-
tic factors for men undergoing HTand though the
trials are designed to look at different aspects of
HT, themes have started to emerge.
Stratification factors for HT
Trials looking at the effects of HT are increasing
in popularity as the treatment modality is becom-
ing more utilized. To date, there have been no
trials examining the effects of HT on subgroups
of patients based on clinical or pathological char-
acteristics (such as GS, PSA level, etc). However,
as research efforts have increased, trends have
started to emerge. These results and future
trials may help physicians determine who will
gain the most benefit from HT. Below is a sum-
mary of some of the factors found to be predictive
of HToutcomes. A complete list of findings from
trials is seen in Table 1.
PSA-related factors. While PSA levels have been
shown to predict PSAR and prostate cancer spe-
cific mortality (PCSM), few studies have specifi-
cally examined the predictive power of PSA as it
relates to HT. A number of studies have found
that PSA-related factors including pretreatment
PSA, PSA nadir level and PSA doubling time
(PSADT) may identify patients at higher risk of
HT failure or PCSM. In a large study that looked
at 1,076 patients with metastatic PCa, Glass and
colleagues found that a PSA<65ng/ml signifi-
cantly predicted 5-year survival in patients receiv-
ing HT [Glass et al. 2003]. A number of smaller
studies have demonstrated that factors such as a
higher PSA nadir after initiation of HT and
PSADT<12 months predict worse outcomes for
men on HT [Choueiri et al. 2009; Chung et al.
Therapeutic Advances in Medical Oncology 1 (2)
86 http://tam.sagepub.com
Page 9
2008; Studer et al. 2008; Scholz et al. 2007;
Tenenholz et al. 2007].
Finally, Hussain, with a cohort of 1,345 men with
metastatic disease undergoing intermittent or
continuous ADT, found thata PSAnadir between
0.2?4ng/ml and PSA nadir <0.2ng/ml were sig-
nificant predictors of survival (HR¼0.30 and
HR¼0.17 respectively) [Hussain et al. 2006].
Though no specific levels have been determined,
data show that a higher PSA level at treatment
time, a higher PSA nadir following treatment and
a faster PSADT (both before definitive treatment
and HT) are all correlated with worse outcomes.
Gleason score. GS is another factor that is con-
sistently found to predict negative outcomes
both before definitive treatment and HT. A
GS>7 is generally regarded as aggressive disease.
Prapotnich and colleagues in a nonrandomized
trial including 566 men on ADT, found that a
GS>7 was predictive of increased mortality
et al.
2009]. Additionally,Ross
Table 1. Summary of risk stratification results from previous hormone therapy (HT) trials.
PaperHT therapyFindings
HT after curative therapy
Glass [Glass et al. 2003]Orchiectomy +/? flutamide
Orchiectomy +/? flutamide
Orchiectomy, LHRH agonists,
anti-androgens or CAB
ADT - No further definition given
GS<8 and PSA<65ng/ml significantly predicted 5 year
African American race, GS>8 and bone pain significantly
predicted lower 5 year survival
High PSA at HT initiation, GS>7, PSA nadir >0.9ng/ml
significantly predicted PCSM
PSA nadir >0.2ng/ml and GS>7 significantly predicted
PSA time to nadir <6 months, GS>7, PSA nadir >0.2
ng/ml predicted shorter overall survival
With metastates GS>7 predicted shorter time to pro-
gression. Without metastases PSA predicted shorter
time to progression. Previous ADT predicted shorter
time to progression for both.
Pathologic stage >T3 predicted PCa specific mortality
PSA nadir >0.05ng/ml and PSADT<12 months were
predictive of PCSM
PSA>4ng/ml before HT initiation was predictive of
disease progression
PSA nadir >4ng/ml after 7 months of ADT, GS>7 and
bony pain was significantly predictive of decreased
Thompson [Thompson et al.
Chung [Chung et al. 2008]
Rodrigues [Rodrigues et al. 2006]
Choueiri [Choueiri et al. 2009]Orchiectomy, LHRH agonists and
Orchiectomy, LHRH agonist and
Ross [Ross et al. 2008]
Porter [Porter et al. 2007]
Scholz [Scholz et al. 2007]
Orchiectomy or LHRH agonist
LHRH agonist +/? anti-androgen
Flutamide with or without
Banez [Banez et al. 2009]
Hussain [Hussain et al. 2006]
HT as primary treatment
Janoff [Janoff et al. 2005]Orchiectomy or LHRH agonists Age<70 and GS >¼6 were found to be at higher risk for
treatment failure
GS >¼7, PSA >¼20ng/ml and a low number of
co-morbidities significantly predicting PCSM
Graff [Graff et al. 2007] Orchiectomy, LHRH agonists and
Intermittent versus
continuous HT
Prapotnich [Prapotnich
et al. 2009]
Irani [Irani et al. 2008]
CAB after primary failureAge<60, PSA >100 and GS>7 were predictive of
mortality in patients undergoing intermittent CAB
Disease progression was associated with PSA and GS.
GS was predictive of PCSM
Immediate versus delayed HT
Studer [Studer et al. 2008]Orchiectomy or LHRH agonistPSADT¼<12 months and PSA>50ng/ml at treatment
initiation were predictive of increase mortality for
patients who underwent delayed ADT
PSA>15ng/ml, PSADT ? 7 months, log of PSADT and log
PSA were predictive of overall survival. Log of PSADT
was significantly predictive of disease specific survival.
HT delayed clinical metastases in patients with GS>7
and PSADT ¼<12 months
Tenenholz [Tenenholz
et al. 2007]
Orchiectomy, LHRH agonist,
anti-androgen, or DES
Moul [Moul et al. 2004] LHRH agonist, orchiectomy or
ADT, androgen deprivation therapy; CAB, complete androgen blockade; DES, diethylstilbestrol; GS, Gleason score; LHRH, luteinizing hormone-
releasing hormone; PCSM, prostate cancer-specific mortality; PSA, prostate specific antigen; PSADT, PSA doubling time.
MA Uhlman, JW Moul et al.
Page 10
found that a GS>7 was correlated with shorter
time to progression in patients undergoing ADT
with metastatic disease, but not in those without
metastases [Ross et al. 2008]. Finally, in a large
trial, Glass and colleagues found that a GS>7
was a significant predictor of decreased survival in
patients undergoing HT [Glass et al. 2003].
As with previously described factors, there is no
GS that has been definitively shown to predict
worse outcomes. However, increasing GS, espe-
cially above 7, has consistently been associated
with decreased survival and treatment failure.
Race. Being of African American (AA) race is a
known predictor of PSAR, but limited studies
have examined race as it pertains to HT out-
comes. In a large trial of 1,263 men with meta-
static PCa who received orchiectomy with or
without flutamide, Thompson and colleagues
found that AA race was a significant predictor
of decreased overall survival [Thompson et al.
2001]. More studies are needed to determine
why this relationship exists.
Summary of risk factors
Based on a limited number of trials reporting
factors predictive of success or failure with HT
as well as a shortage of randomized trials, it is
difficult to make definitive recommendations as
to which patients are best suited for HT.
Nevertheless, emerging trends from available
trials suggest that distinct clinico-pathological
characteristics, including elevated PSA, rapid
PSADT, high PSA nadir following therapy and
GS>7, may give prognostic information as to
which patients are likely to gain the most benefit
from HT. This information and future findings
are likely to lead to risk stratification guidelines
for men undergoing HT for PCa.
HT continues to be a common treatment option
for recurrent PCa and locally advanced PCa.
Both long- and short-term treatment courses
are associated with many undesirable side effects
which can lead to decreased QOL. There are only
a few circumstances in which HT is clearly
(1) For patients with high risk disease that are
undergoing radiation therapy;
(2) To shrink the prostate before brachytherapy
(though there has been no survival advan-
tage demonstrated); and
(3) To palliate symptoms in patients with meta-
staticPCa [Heidenreich
Thompson et al. 2007].
et al.
Treatment with anti-androgens has been shown
to be inferior to ADT for patients with metastatic
disease [Tyrrell et al. 1998]. For patients with
recurrent diseaseafter
there is little data suggesting a survival advantage
from the use of HT, however much data exists to
support the palliate ability of the treatment.
Both LHRH agonists and anti-androgens are asso-
ciated with significant side effects. Treatments
with anti-androgens have much lower rates of
sexual side effects, hot flashes and osteoporosis.
Anti-androgens are also not known to cause bio-
chemical flare. Treatment with ADT results in
lower rates of gynecomastia and breast tenderness.
Emerging research has shown that HT may be
associated with increased rates of metabolic and
cardiac complications as well as cognitive declines.
CAB has been shown to produce a small, but
significant increase in overall survival, but cost
considerations and side effects should be taken
into consideration.Treatment
antagonists and TAB are not well studied.
Questions remain as to the best time to initiate
treatment, the optimal duration, the best treat-
ment schedule and most importantly, which
patients are the most likely to benefit from HT.
Patient stratification based on clinical and patho-
logical factors remains ambiguous and though
results from trials are limited, some trends have
started to materialize. Patients undergoing HT
and with characteristics including a PSADT
?12 months, GS>7, PSA nadir >0.2ng/ml and
elevated PSA at time of HT may be at increased
risk of disease progression and ultimately PCSM,
though additional studies are needed to confirm
these initial findings.
In the end, communication is paramount in
determining optimaltherapy
patients. Before initiation of HT, clinicians
should carefully consider the factors that have
been shown to correlate with poor HToutcomes,
and patients should be made aware of the poten-
tial adverse effects and risks associated with dif-
ferent HT treatment options. This combination
of efforts gives patients and providers the best
chance at achieving the optimal balance of risk
and benefit.
Therapeutic Advances in Medical Oncology 1 (2)
Page 11
The author Matthew Uhlman wishes to acknowl-
edge the NIH Grant TL1 RR 024126.
Conflict of Interest Statement
None declared.
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Page 13
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text:
Lindsay Lohan: In the Morgue, Seeing Dead Folksby Free Britney at . Comments
Lindsay Lohan dressed like a ghost in court the other day.
Oddly fitting, given that she'll be doing community service at the morgue.
The troubled star won't be touching any dead bodies while putting in her time at the L.A. County morgue ... but staring them in the face is par for the course.
Lindsay Lohan: Dressing in character for her stint at the morgue?
Lindsay is on sheet-washing duty and covered her mouth in horror when she first laid eyes on a not-living human and his/her blood and fluid stained linens.
According to reports, she saw the dead body in the morgue and was "shocked." Lohan has since moved on to toilet duty, a separate part of her duties there.
Despite that rude awakening, she is said to be good spirits, talking to other people in her group and maintaining a positive attitude. Make this is for the best.
Lindsay has been ordered to complete 16 hours in the morgue a week until her November 2 hearing. Yesterday, she was turned away after showing up late.
She may face real jail time at that hearing. Should she get it?
[Photo: WENN.com]
i love her she doesnt need jail she needs freedom
she is beatiful but she doesnt need jail sh needs freedom people
the little brat deserves jail, but let's be real it's a WASTE of tax payer money. she'll go in for 1 day and be let free because there are real criminals (i.e. people who are actually a danger to society). Lindsey is only a danger to herself - let her do what Amy Winehouse did - o/d herself to death. and make her pay fines out the ass to at least give the city if LA some much needed money
Lock her up with no special cell, or favors, or brought in food, put her with the rest of the bad girls, and see what rank she pulls in jail, she will see what its like with nothing, but your toothbrush , bar of soap, and a plastic spork for your 4 am cold oatmeal, no sugar!! follow orders or ass whoopin, them are the options
I blame her fucked up parents....who talk shit about her and used her and tore her down....I think she needs serious help not jail... jail is not working for her...The girl is not right in the head...She used to be so Beautiful... and she so messed up now she dont even care anymore about her looks...I dont think she'll ever become what she once was and I semi feel sorry for her and i truly dislike both her parents
She looks dead hope she dont think she is hot
Oh America! Our sick little game of controlling people's live. Worship the movie star then tear them down and feed them to the lions. Making money on both ends.
Wat the heck y did they leave that brat to go outa jail
are are the black spots on her cheeks?
Lohan is not learning from her mistakes. enough said. maybe she needs psychological help.

subset: commoncrawl


text:
Egg in a Basket
Cook this egg-filled bread slice until golden brown then top with Swiss cheese, avocado, and tomato for a nutritious breakfast, lunch, or dinner. Easy!
- Makes:
- 1 servings
- Start to Finish:
- 25 mins
Rate me!
Egg in a Basket
slice white, whole wheat, or raisin bread
tablespoon milk
Dash salt
Dash pepper
tablespoon margarine or butter
slice Swiss or other cheese
Avocado slice (optional)
Tomato slice (optional)
- Cut a hole 2-1/2 or 3 inches in diameter from the center of bread slice. Reserve center round. In a small shallow flat dish combine one of the eggs, milk, salt, and pepper. Dip bread slice and center round in egg mixture.
- In a medium skillet melt margarine or butter over medium heat. Cook dipped bread slice and center round in margarine about 1 minute on each side or until light golden brown. Drop remaining egg in center of slice and cook until egg is almost of desired doneness. Turn over and top with cheese. Cook about 1 minute more or until cheese is slightly melted. (For an egg cooked sunny-side up, cook for 2 minutes, and cover skillet after adding cheese slice.) Garnish with avocado and tomato slices, if desired. Makes 1 serving.
Nutrition Facts(Egg in a Basket)
- Per serving:
- 430 kcal cal.,
- 30 g fat
- (10 g sat. fat,
- 5 g polyunsaturated fat,
- 13 g monounsatured fat),
- 452 mg chol.,
- 614 mg sodium,
- 15 g carb.,
- 1 g fiber,
- 2 g sugar,
- 23 g pro.
- Percent Daily Values are based on a 2,000 calorie diet


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We have a new Archbishop in the Anglican Church of North America: Author: George Conger The House of Bishops of the Anglican Church in North America (ACNA) has elected the Rt. Rev. Foley Beach as its second archbishop in succession to the Most Rev. Robert Duncan. Meeting in a private conclave at St Vincent College [Read More...]
Rt. Rev. Foley Beach, new Archbishop
Jun 22, 2014 @ 15:25 by Leave a Comment
My Anglican Journey
Apr 9, 2014 @ 0:05 by Leave a Comment
Beginning at 10am on April 26 in a service at the Church of the Redeemer (Highland Park) I will be ordained into the Sacred Order of Deacons. I grew up among America's Baptists (CBofA), attended Cornerstone University (GARB sponsored at the time), went to TEDS (EvFree) and then did my doctorate at Nottingham, began my teaching [Read More...]


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I bought this product because of the great reviews I heard about it and because it is free of a lot of the fatty alcohols that other moisturizers have. I have combination skin - oily in the t-zone but dry along chin (due to acne medication) and under eyes. I love the consistency of this product. It has a lovely gel-like feel. But it does NOT moisturize enough. Even after two layers of it I still have dry patches around my chin area. It really feels as if I have not put anything on. I'm a little disappointed in this moisturizer for the price and will not repurchase.
Edit: I originally wrote this review in the winter. Now that the weather is warmer, I can get away with applying two pumps of the gel and walking away with soft skin but I still don't feel completely moisturized.
1 out of 1 people found this review helpful. Did you? Yes No
I bought this due to recs on the skin care board (many really know their stuff on there btw). I have oily, but sensitive skin and I was looking for something to hydrate my skin without being too heavy for my acne and clog-prone skin. This has a nice light texture, almost liquidy and you only need a little bit. It applies smoothly and really helps to soften my skin. In essence it is a no frills moisturizer so I can use it at night too. I wore this under my foundation with no problems. It also doesn't make my face an oil slick throughout the day and I find it such a relief that it doesn't break me out. I can't believe I didn't get this sooner. I would have saved myself money and the hassle of finding a good moisturizer suitable for my skin. I got my small tube at Ulta since I had a coupon and had some points to redeem so it ended being cheap for me. I think it is about 14-15 bucks otherwise.
I use this moisturizer in the summer when my skin doesn't need as much hydration. I put this on then layer clean and clear hydrating gel moisturizer overtop. It's the perfect amount of hydration for my oily combo skin that absorbs quickly and doesn't feel or look greasy since it's a gel. Doesn't break me out either and I love the pump so I don't waste product. This formula is really best for oily skin. If you have dry skin I wouldn't recommend. I'll continue to repurchase.
i detest clinique clarifying lotion as it aggravates my acne. but i am still using the ddmg mainly because it is so good that it does what it claims. fast absorbing and did not break me out
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I recently changed over from the Moisture Surge to this one and I feel they both moisturise my skin in the same way. The consistency is very similar (both are gels) and they feel lightweight on the skin and not greasy at all. My skin type is generally oily in the T-zone and normal-ish everywhere else, so I prefer this over a lotion/cream any day. I also like how this one comes in a bottle with a pump rather than a jar. However, for night-time I will probably purchase a different moisturiser as I feel this is better for day-time use under my makeup or on its own.
Since using this moisturiser, I have had no breakouts or dry patches on my skin so I am really impressed with it. I didn't get any with the MS so I guess they are very similar in how they work for my skin.
The main reason for switching over would be the overall cost, this is a few pounds cheaper than Moisture Surge but you get over double the amount (I went for the 125ml bottle) so I'm thinking it will last twice as long!
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This definitely isn't the most moisturizing product. If you have super dry skin & you're looking for something to smooth out dry patches, this isn't your moisturizer. However I have combination to oily skin that stays hydrated by using a mask once a week. This helps keep my face moisturized & really helps keeps me less oily. So if you have oily skin & you're looking for something to help control that this is definitely it. However, I won't be repurchasing because for the money I'm sure there has to be a better moisturizer. This will be great for summer tho.
1 out of 1 people found this review helpful. Did you? Yes No
This is a nice moisturizer for really oily skinned girls because it's really light and doesn't feel that moisturizing. This is also a really nice moisturizer for underneath makeup as it creates a smooth base. I won't repurchase because I don't really have a use for it except when I'm going out at night and need to put makeup on (or else I'm using SPF moisturizer for the day or an acne fighting or richer moisturizer for night).
I've almost run through the bottle. For me, this is far from being an effective moisturizer. My skin is oily, so this was recommended to me with fervor. I do like that it absorbs quickly, but after five minutes, it's like I haven't put anything on. My face feels tight, slightly itchy (the itch that comes with being too DRY), and flaky. My skin, though oily, is dry - dehydrated (I know I don't drink enough water).
This stuff simply doesn't do the job. I'm trying out their dramatically different lotion to see how it works out. So far it has done what I need it to do.
2 out of 2 people found this review helpful. Did you? Yes No
Lovely light but hydrating gel moisturiser for my slightly oily, combination & spot prone skin. I really like that it's oil free & not greasy, it works very well as a base before make-up. Before I purchased this I tried a sample of the lotion but it was greasy and left a film on my face - in my opinion the gel is much better :-) My only negative is the price, £30 is very expensive for a moisturiser, I just hope it lasts a long time for that price!!
The Clinique sales assistant recommended this to me after I told her that I had fairly dry skin, however I sometimes get oily in the T-Zone in summer. (She gave me a sample.)
After cleansing and toning, I applied the gel which is a good consistency, leaves your skin feeling soft, sinks into the skin immediately and doesn't leave a film or leave your skin greasy.
However after a few minutes I could feel my skin feeling really dry again and I'd have to moisturise with a different moisturiser.
This moisturiser is definitely more for combination/oily skin and will not help you if you have dry skin.
It simply did not work for me, however it could be a nice product if you have oily skin.


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Err, Don't they need to manually connect to that network? Through network connections etc. If so can't you just disable access to that as normal?
I've found out that a member of staff has been tethering his android through USB and using 3G to bypass the filtering. Whilst he may be trustworthy lots aren't and if the laptop users (6th form and staff) get wind of it our filtering becomes worthless. not wanting to drop him in it can anyone think of an easy way (GPO?) to prevent tethering preferably without anyone even knowing?
Err, Don't they need to manually connect to that network? Through network connections etc. If so can't you just disable access to that as normal?
The example I tried was - set up Proxy Switcher extension in Google - set up Willkommen bei Facebook - anmelden, registrieren oder mehr erfahren as a rule to just go to direct connection 9i.e bypass proxy), plug phone in tethered to usb.
Browse to facebook - it somehow goes straight to the phone!
(We've historically let 6th formers and staff be local admins on their machines)
how on earth did that link become german? www . facebook . com
There are some GPOs that disable connection to remote connections, assuming it'd count as one of them?
Configure network connection restrictions with Group Policy
e.g. Prohibit connecting and disconnecting a remote access connection. If you enable this Group Policy setting, then affected users cannot connect by using any remote access connection, or disconnect any that are currently connected.
But if they have local admins not sure if the GPOs will do what you want anyway. Is there any reason they are allowed to install extensions etc anyway?
Put it in the AUP that using tethering to bypass internet filtering is not allowed and then pick him up on it - to be honest I can't see a technical solution to this but then again it shouldn't be a technical issue in the first place - its a disip/user issue.
On Meru wireless set rogue AP detection and mitigation, it stops portable hotspots working
This is a USB connection into the machine not through wifi.
Those GP's are worth a try. I'll have a play.
It's all very well having a school policy which says x,y and z. But no-one listens and certainly doesn't bother about them! Just taken over 20 smashed keyboards and 2 smashed monitors out of one IT room - what happened to the culprits? yep - nothing.
You're right of course re giving them admin rights - it just made life easier - like most things, it bites you eventually. I think over Easter this member of staff may find he can't do what he used to be able to......
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Are these medications keeping me from losing weight: Zyprexa, Vistaril, and Lamotrigine?
- Q: I am taking Zyprexa, Vistaril and Lamotrigine. Can you tell me if these are the source of my not being able to lose weight. I excersise and watch my diet and I have packed on a whopping 15 lbs since starting them a year ago. I don't want to quit taking them but would like to know if there might be one that I could stop. I was diagnosed as bipolar in 2009.
- A: In clinical studies, weight gain occurred in 30% of patients taking the antipsychotic medication Zyprexa (olanzapine). Other common side effects of Zyprexa include: back or joint pain, dizziness, drowsiness, constipation, dry mouth, increased appetite, indigestion, numbness of the skin, restlessness, sore throat, and weakness. The antipsychotics least likely to cause weight gain are Abilify (aripiprazole) and Geodon (ziprasidone). The anticonvulsant Lamictal (lamotrigine), has been reported to cause weight loss, and Vistaril (hydroxyzine), an antihistamine, should have no direct effect on weight. But, Vistaril can cause drowsiness which may make exercise more difficult. Drugs can cause weight gain in several different ways. Some can increase appetite or make you crave certain types of foods like those high in carbohydrates or fat. Other medications may slow down metabolism or cause fluid retention. Most prescription medications associated with changes in body weight affect the central nervous system. These include antidepressants like monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs), mood stabilizers (lithium, valproic acid), antipsychotics, and anticonvulsants. If you think a drug you are taking is causing weight gain, tell your health care provider. Do not stop any medication or change the dose without first talking to your physician. For information about bipolar management, check out the following link: www.everydayhealth.com/health-report/bipolar-depression/staying-healthy-with-bipolar-disorder.aspx Burton Dunaway, PharmD
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