Oottamasathien and Crawford
advance a hypothesis with
which I heartily agree-androgen
strategies should be considered in many
more patients than urologists and oncologists
traditionally teach. However,
I think the authors could substantially
sharpen their message. I would like to
make five specific points, and then
offer a few nitpicking comments.
Redefine Advanced Disease?
The authors suggest that we need
to redefine what we consider to be
advanced disease. I disagree with this
suggestion. Redefining "advanced"
disease may be emotionally and subjectively
really want to tell our patients that
their disease is worse? I think not.
We desperately need to apply the
risk assessment tools currently available
and recognize that the risk of prostate-
specific antigen failure equals
neither the risk of detectable metastatic
disease nor the risk of prostate mortality.
We must use these tools to define
patients in whom randomized, adequately
powered studies of AD/A are
conducted. Then we must convey the
concept of risk and the areas in which
we lack knowledge to our patients.
It is instructive to remember that
our colleagues who care for women
with breast cancer did this 40 years
ago-systemic adjunctive studies
of estrogen deprivation/antagonists
(ED/A) as well as cytotoxic agents were
begun in the late 1960s in women
with breast cancer. Risk assessment to
judge entry in these studies employed
nodal status, tumor size, menopausal
status, and, more recently, biochemical
characteristics (estrogen and progesterone
receptors, HER2/neu). Tens
of thousands of women have entered
studies comparing ED/A strategies vs
placebo, cytotoxic therapy with or without
ED/A, and biologic agents (trastuzumab
[Herceptin]) and alternative
forms of ED/A. What have we done in
terms of comparable studies in men
with prostate cancer? Very little.
Message of the VA Cooperative
In my view, the Veterans Affairs
(VA) Cooperative Group studies, conducted
in patients staged only with
plain radiographs, acid phosphatase,
and physical exam, and in which
crossover to AD/A was unregulated
or monitored, represent the first-and
perhaps the best-trials we have done
in prostate cancer. They are the best
because they entered large numbers
of men in a randomized setting with
state-of-the-art trial designs. Given
methodologic improvements that have
occurred over the past 40 years, the
failure of the VA Cooperative Urological
Research Group (VACURG)
studies to prove a long-term survival
advantage with AD/A strategies
should not be assumed to mean that
these approaches are of no use.
Best Approach to AD/A
From the Patient's Perspective
The authors present a logical inconsistency
in our current approach.
Cassileth et al (Oottamasathien and
Crawford's reference 13) suggest that
men prefer luteinizing hormone-
releasing hormone (LHRH) analogs
to orchiectomy (in a study funded by
an LHRH analog manufacturer), but
Potosky et al (their reference 14) report
more sexual dysfunction with
LHRH analogs than orchiectomy. This
issue should be reassessed, and we
should recognize that:
- No substantiated data have yet
proven the superiority of intermittent
vs continuous AD/A. Therefore, the
merit of the reversability of LHRH
analog-induced castration is uncertain.
- It takes a considerable amount of
time to really discuss surgical castration
compared to LHRH analogs.
- There are incentives other than
our patient's psychological and sexual
well-being that have an impact on
the choice of AD/A strategies.
Can Studies of Irradiation ± AD/A
Be Challenged for the Lack of an
AD/A-Only Control Arm?
I think not. That design would address
a different issue than the one at
hand. The studies of the European
Organization for Research and Treatment
of Cancer (EORTC) and
Radiation Therapy Oncology Group
(RTOG) asked a straightforward and
carefully framed question-does adjunctive
AD/A improve outcome in
high-risk localized prostate cancer?
The answer is an unqualified yes.
At the recent American Society of
Clinical Oncology meeting, Pilepich
reported the more mature results of
RTOG 85-31. Survival and prostate
cancer-specific survival were superior
for irradiation (P < .001) with LHRH
analog compared to irradiation only. In
certain high-risk groups, AD/A improves
survival obtained with irradiation.
The role of AD/A alone and more
precise definition of the risk subgroups
who benefit will require other studies.
But to this reviewer's eye, the overall
answer is clear.
Does AD/A Cause Osteoporosis?
The authors assert that "multiple
groups argue that men receiving hormonal
therapy do not have significantly
lower bone mineral densities
than age-matched controls" (an assertion
supported by a single reference
to an abstract). I heartily disagree. To
the contrary, there are multiple groups
who have reported clear differences
in bone mineral density (BMD) in
men who have undergone AD/A.
The Mayo Clinic group recently reported
a substantial increase in fracture
risk among castrated men with prostate
cancer compared to age-matched controls.[
3] Intermittent AD/A has been
shown to have a lesser impact on BMD
than continuous AD/A, and bisphosphonates
bone loss. AD/A use is clearly associated
with an increased risk of osteoporosis,
and osteoporosis-at least in
women, in whom it has been adequately
studied=is associated with increased
fracture risk. Hip fractures in elderly
patients are associated with a 25%
30-day mortality. We must consider
this risk as we decide in whom and for
how long to employ adjunctive AD/A.
Several other points merit attention;
the reader is referred to the appropriate
literature for a more complete and
- The role of high-dose antiandrogen
monotherapy and the blockade of
gynecomastia by antiestrogens.
- Why was the outcome of the
LHRH analog with or without antiandrogen
trial different from that of the
orchiectomy with or without antiandrogen
trial? Was it the "flare," or
was it the fact that the LHRH analog
was to be given by the patient daily?
My biggest concern for this entire
area of research is that we are performing
in a shameful manner, as far as
entry of patients in randomized trials of
important and well-tolerated adjunctive
strategies. We can assess risk. We
have well-tolerated and safe adjunctive
strategies, but we have barely scratched
the surface when it comes to asking
and answering the critical questions.
We vitally need to initiate the right
trials. We should look to the record
achieved in the adjunctive therapy of
breast cancer, not to mention colorectal
and most recently lung cancer, for
guidance. As Pogo said, "We has met
the enemy....and he is us."
1. Pilepich MV, Winter K, Lawton C, et al:
Phase III trial of androgen suppression adjuvant
to definitive radiotherapy. Long term results
of RTOG study 85-31 (abstract 1530).
Proc Am Soc Clin Oncol 22:381, 2003.
2. Smith MR: Diagnosis and management
of treatment-related osteoporosis in men with
prostate carcinoma. Cancer 97(3 suppl):789-
3. Melton LJ 3rd, Alothman KI, Khosla S,
et al: Fracture risk following bilateral orchiectomy.
J Urol 169:1747-1750, 2003.
4.Boccardo F, Barichello M, Battaglia M,
et al: Bicalutamide monotherapy versus flutamide
plus goserelin in prostate cancer: Updated
results of a multicentric trial. Eur Urol
5. Iversen P, Tyrrell CJ, Kaisary AV, et al:
Bicalutamide monotherapy compared with castration
in patients with nonmetastatic locally
advanced prostate cancer: 6.3 years of followup.
J Urol 164:1579-1582, 2000.
6. Boccardo F, Rubagotti A, Garofalo L, et
al: Tamoxifen (T) is more effective than anastrozole
(A) in preventing gynecomastia induced
by bicalutamide (B) monotherapy in
prostate cancer (pca) patients (pts) (abstract
1608). Proc Am Soc Clin Oncol 22:400,
7. McLeod D, See W, Iversen P, et al: Immediate
bicalutamide 150 mg therapy significantly
reduces the risk of disease progression
in patients with localized prostate cancer who
would otherwise be candidates for watchful
waiting (abstract 1629). Proc Am Soc Clin
Oncol 22:405, 2003.