The Current State of Hormonal Therapy for Prostate Cancer,
Beth Hellerstedt & Kenneth Pienta
In general androgen deprivation induces
a remission in 80 to 90 percent of men with advanced prostate
cancer, and results in a median progression-free survival of 12 to 33 months.
At that time, an androgen-independent phenotype usually emerges, leading to a median overall
survival of 23 to 37 months from the time of initiation of androgen deprivation.
The first VACURG study, published
in 1967, randomized 1,764 Stage III and IV patients to one of four treatment options: placebo, orchiectomy
plus placebo, DES 5 mg per day, or orchiectomy plus DES 5 mg per day.8 Orchiectomy was associated with a one-year survival rate of 73 percent
and a five-year survival rate of 35 percent in Stage IV patients, compared with 66 percent and 20 percent
in placebo-treated patients. 15% more survived 5 years and 7 % more 10 years.
Diethylstilbestrol (DES), a semi-synthetic
estrogen compound, was one of the first nonsurgical options for the treatment of prostate cancer. Widespread use has been limited, however, by the potential
for significant cardiovascular and thromboembolic toxicity. Initial
studies from VACURG and the European Organization for Research and Treatment of Cancer (EORTC) used 3 to 5 mg of
DES per day, and showed the remission rate of DES to be equivalent to orchiectomy. DES at a dose of 3 mg per day has also shown equivalence to LHRH agonists in patients with locally
advanced and metastatic disease in terms of overall survival and subjective improvement. DES proved to be superior to flutamide alone in the treatment of metastatic disease.22 Several EORTC trials (30761 and 30762) demonstrated DES 3 mg per day to be
equivalent to estramustine23 and cyproterone.24 The introduction of the LHRH analogs, with no significant cardiovascular
toxicity, lack of breast enlargement, and significant reimbursement for clinicians, essentially ended
the use of DES as a first-line hormonal therapy. DES is no longer mass produced for human use in the United
Meta study of 8,275 patients with metastic cancer had a survival rate of 25.4%, 23.6% for montherapy. The five-year
survival for all patients receiving CAB was 25.4 percent compared with 23.6 percent for patients receiving
The authors concluded that neoadjuvant
androgen deprivation before radical prostatectomy
was not indicated.
The retrospective review of
the Mayo Clinic data included 707 men who underwent prostatectomy
for Stage pT3bN0M0 disease, 147 of whom received adjuvant hormonal therapy (orchiectomy or oral hormones).
Adjuvant therapy was associated with a significant improvement in biochemical progression-free survival
(67 percent versus 23 percent at 10 years), systemic progression-free survival
(90 percent versus 78 percent) and cause-specific survival (95 percent versus 87 percent). Which is to state a lower replace rate of 12%.
The Eastern Cooperative Oncology
Group (ECOG) randomized 98 men with positive lymph nodes at the time of surgery to receive immediate
antiandrogen therapy (with either goserelin or orchiectomy) or to be followed until disease progression.45 After 7.1 median years of follow-up, 7 of 47 men who received immediate
antiandrogen treatment had died, as compared with 18 of 51 men in the observation group (p = 0.02).
In the adjuvant group, three men died of prostate
cancer, compared with 16 men in the observation group. Very significant survival for those on antiandrogen therapy.
Interest has been increasing in the
use of nonsteroidal antiandrogens as adjuvant therapy in patients with localized disease.46 Early results of a study of 365 patients with pT3N0 disease investigating
the efficacy of flutamide (250 mg twice daily) given after radical prostatectomy demonstrated a 10% clinical recurrence
rate at four years in the flutamide-treated patients compared with a rate of 31 percent for those receiving
placebo (p = 0.002).
There are 3 zones, the peripheral
zone accounts for 70% of the volume, central zone 25%, transition zone 5%. Percentages
of carcinoma are approximate the based on volume. About 40% of the deaths from prostate cancer occur in men over 80 years.
Radiation therapy is preferred if complete surgical removal of the tumor is unlikely. A Gleason
score of 7 or higher, a PSA level greater than 20, or evidence the tumor has penetrated the prostate capsule (stage T3) is
an indication for primary radiation therapy.
HORMONE THERAPY IN CONJUNCTION WITH EXTERNAL BEAM RADIATION THERAPY
In 1997, the EORTC reported the results
of 415 patients with locally advanced prostate
cancer treated with external beam radiation versus external beam radiation plus goserelin for three
years.50 At a median follow-up of 45 months, the Kaplan-Meier estimates of overall
survival at five years were 79 percent for patients who received combined treatment versus 62 percent in
the group treated with external beam radiation therapy alone (p = 0.001).
Eighty-five percent of surviving patients were free of disease at
five years in the combined-treatment group and 48 percent in the group that received external beam treatment
alone (p < 0.001). These data strongly suggested that adjuvant treatment in patients with locally
advanced prostate cancer improved both
local control and survival at five years. 85% DISEASE FREE VERSUS 38 WITH HORMONE THERAPY. How ever other studies
have revealed no improvement for those with 7-10 tumors, but 18% advantage for
those with 2 to 6 tumors.
BRACHYTHERAPY (radiation placed close to the surface of the body or within a body cavity.
Stone and colleagues biopsied a series of 296 patients, 115 of whom received complete androgen blockade
for three months prior to implant and for three months after implant.57 Biopsies were positive in 4 of 115 (3.5 percent) who had received androgen
deprivation versus 26 of 181 (14 percent) in those who had not (p = 0.002). When patients were separated
into low risk (PSA < or = 10 ng/ml, Stage < or = T (2a), and Gleason score < or = 6) and high
risk (all others), it was observed that low-risk patients did not benefit from the addition of hormonal therapy
while the high-risk patients not treated with androgen deprivation had a significantly higher rate of positive
biopsies (3.4 percent versus 21.1 percent; p = 0.003). However, the next study failed to demonstrate an advantage for hormone therapy—conclusion
was “remains unclear.”
Side Effects of Androgen Deprivation Therapy
therapy was considered to be well tolerated. Loss of libido was often the only adverse side effect mentioned
to the patient. Several other toxicities have now been noted (Figure 4 ). These include fatigue,65 weight gain,66 depression, osteopenia,67 anemia, muscle atrophy, gynecomastia,68 hot flashes,69 loss of cognitive function, and decrease in high-density lipoprotein.
Once initiated, most men remain on hormonal
therapy for years, if not the rest of their lives. Long-term treatment with androgen deprivation can
lead to debilitating osteoporosis.72,73 Even in a study of inter-mittent androgen blockade, evaluation of bone
mineral density in the lumbar spine and hip revealed osteopenia in 46 percent and osteoporosis in 20 percent of
patients.74 A similar study found that 50 percent of men on androgen blockade
for at least 12 months had asymptomatic vertebral fractures.75 The precise incidence of clinically relevant fractures remains
the study was only of a 48-week
duration, it underscored the startling amount of bone loss in patients on leuprolide alone for this period: 3.3
percent in the lumbar spine, 2.1 percent in the trochanter, and 1.8 percent in the total hip.
Cost also enters into decision-making
when considering monotherapy versus CAB. A recent study evaluated the cost-effectiveness of different
types of androgen ablation (DES, orchiectomy, medical monotherapy, and CAB), incorporating a quality-of-life analysis.97 Orchiectomy, LHRH agonists, antiandrogens, and CAB had similar
effects on quality of life and survival estimates. The annual cost estimates included: DES: $36, LHRH agonist
depot injection: $4,995, and antiandrogens: $2,842. Orchiectomy had a one-time cost of $3,360. CAB was
associated with the smallest degree of benefit for the most relative cost. In this study, the lifetime cost
of an antiandrogen plus orchiectomy was $20,700, while the cost of an antiandrogen plus LHRH agonist was $40,300.
Figure 6 illustrates the relative lifetime costs of each therapy in comparison to effectiveness.
Data from multiple studies
support a growing trend to treat patients earlier in their disease course, but currently, there is no
single correct answer regarding timing of hormonal therapy for patients with PSA progression or asymptomatic metastatic
Cost and patient preference may assist
in this choice. DES is available in the United States,
but only from a few pharmacies. Because of cardiovascular toxicity, DES may be best reserved as a secondary
hormonal option. Some patients may opt for alternative strategies, such as nutritional therapy or herbal supplements.
1989 August J Urology , 332-6
Node metastases & dying risk
negative nodes 31% metastases & dying of prostate cancer17% at 10 years
single microscopic positive node
risk of distant 80% & dying of 40%
multiple microscopic positive nodes,
84% & dying 66%
grosly or juxtaeregional nodes, 88%
& dying 58%
Once prostate cancer is found within
the pelvic lymph nodes the patient has systemic disease unlikely to be controlled by pelvic lymph node dissection and radiotherapy.
JAMA. Vol. 277 No. 6, Feb 12, 1997.
15 year study of men in Sweden
average age 72 with prostate cancer. 642 patients all stages followed up until
1994. Of the 541 deaths, prostate cancer accounted for 201 (37%). Those with localized disease 11%; those with deferred treatment in this group had a similar survival rate
to those who received initial treatment. For those with locally advanced (T3-T4)
the survival rate was
57%. Those with distant metastases at the time of diagnosis the survival rate was 6%. Conclusion for those with localized prostate cancer and without a reliable prognostic indicator, aggressive
approach would result in substantial over treatment.
NATIONAL CANCER INSTITUTUE AT http://www.cancer.gov/cancertopics/treatment/prostate/hormone-therapy-use
Which urologist a patient with prostate cancer chooses may be more important in determining whether he
receives hormone therapy than other factors such as his age or type of tumor, a new study reports.
"The urologist seems to play a role that is at least
as important, if not more important, than tumor grade and patient characteristics," says lead researcher Dr. Vahakn B. Shahinian
of the University of Texas Medical Branch
The findings suggest that a patient could go to two
urologists and receive different opinions about whether to have the treatment, called androgen deprivation therapy because
it blocks androgen hormones such as testosterone.
"This scenario is cause for concern because patients
might be getting therapy that may not be in their best interest," says Dr. Shahinian.
Approximately half of all prostate cancer patients
receive the therapy over the course of their disease. When given with radiation, the therapy can extend the survival of patients
with locally advanced disease.
But there are not clear data for urologists to follow
about when androgen deprivation therapy should be used for other patients. The treatment is expensive and potentially toxic,
with side effects such as an increased risk of fractures and loss of sexual function.
During the 1990s, there was a dramatic increase in
the use of androgen deprivation therapy for prostate cancer, even in cases where its benefit was unproven or highly improbable.
This in part led to the new study.
The researchers linked the Surveillance, Epidemiology, and End Results (SEER) and Medicare databases to identify 1,800 urologists who treated 61,000 men diagnosed
with prostate cancer at age 65 years or older. The most recent data were from 1999.
The urologist was responsible for about 20 percent of the
variation in the use of hormone therapy, versus 10 percent for tumor grade and stage, and 4 percent for patient characteristics,
according to findings in the June 21, 2006, issue of the Journal of the
National Cancer Institute (JNCI). (See the journal abstract.)
Dr. Shahinian and his colleagues have begun to try
to identify the characteristics of urologists that cause them to select the treatment.
A limitation of the study was the lack of information about
prostate-specific antigen ( PSA) levels in participants. Rising PSA levels can be an indication for the therapy,
so some patients might have received it based on evidence rather than physician judgment.
Nonetheless, the study shows that a powerful anticancer
therapy is often selected based on a physician's intuition rather than on hard facts or evidence-based medicine, says Dr.
Paul Schellhammer of Eastern Virginia Medical
School, who wrote an editorial in JNCI.
Prostate cancer is an extraordinarily heterogeneous
disease, and many cancers are diagnosed that will not affect the length or the quality of a man's life. "But hormone therapy
represents a powerful remedy for patients who have progressive disease," Dr. Schellhammer adds.
The challenge for physicians, he suggests, is to
offer androgen deprivation therapy to men with high-risk, potentially lethal prostate cancer early in their course of treatment
and to withhold it from men with low-risk disease, thereby avoiding unnecessary risks.
Clinical trials are under way to clarify the picture
of how and when the therapy should be used. Dr. Schellhammer predicts that a day will come when the treatment's use is guided
by physicians but based on evidence rather than directed by physicians, as it is today.
Int J Radiat Oncol Bio Phys. 2005 Aug 1; 62(5): 1322-31
Lack of benefit from short course of androgen deprivation for unfavorable prostate cancer patients treated
with an accelerated hypofractionated regime. 1260 patients were treated with
HDR prostate brachytherapy PSA ./= 10, Gleason score >/= 7 and .>/= T2b. The
androgen therapy did worse—possible because of delay in treatment with brachytherapy.