If you were depressed by Dr. Walsh's views read on...

As more men are diagnosed with earlier stages of prostate cancer
including
earlier stages of advanced prostate cancer, less men present with
multiple
lymph node or bone mets at diagnosis. This implies significantly less
tumor
burden and an opportunity for early hormone suppression to induce
massive
cell death in the androgen dependent portion of the tumor load.

For many years, the medical profession had evidence that demonstrate
that
the lower the tumor burden the better the response to hormone
suppression.
This was clearly demonstrated by Crawford ED et al(7). In this
study, men were stratified by the degree of their cancer progression.
The
response to combined hormone suppression was as follows:
1. Advanced with major symptoms such bone pain, weight loss etc.
responded
for 8.5 months.
2. Advanced with minor symptoms, responded for 15.4 months.
3. Advanced with disease limited to lymph nodes, response was 4 years.

In this study, done more than a dozen years ago, even a significant
number of the
patients in the first group were responding after 4 years (about 10%).
About
30% to 40% of the patients with disease limited to lymph nodes were
still
responding after 10 years.

This is a clear indication that deprivation response is directly
proportional to the
degree of disease progression at the time of diagnosis and the tumor
volume
ratio of androgen dependent/androgen independent cells.

More evidence of this is supported by Labrie et al (9) in a study in
which response
to androgen deprivation was correlated to the number of bone lesions
at the
initiation of therapy. Men with 5 or less bone mets had the longest
response.

These are known biological facts. Androgen dependent tumor cells die
when
deprived of  androgens while androgen independent cells survive. Why
would
anyone allow  androgen dependent cells to become androgen independent
when
they could be killed by androgen deprivation applied early on in the
first place?

Hormone suppression is known to prolong time to progression, but is
it
possible that it could also extend survival? There are a number of
studies
in which results indicate that early disease detection and early
hormone
suppression not only postpone disease progression but also improves
survival.
This is something that *fits* in the overall picture of explaining the
32.5% reduction
in mortality experienced in the U.S.A. since the mid nineties.

The old myth that patients diagnosed with advanced prostate cancer
only
respond to hormone suppression for a year or two is simply a myth. In
this
age of early detection and of earlier stages of advanced prostate
cancer at
diagnosis this myth is no longer supported by the current medical
literature. This myth perseveres because of doctors that believe that
saving
hormone suppression for later when bone mets develop is perfectly
fine. This
IS NOT supported by current medical evidence.

The real question then is the value of early versus delayed hormone
suppression. In the original VACURG study, DES at 5 mg caused many
vascular
events causing  death. This study did not demonstrate a survival
advantage
and in retrospect caused many clinicians to abandon the use of
estrogen
for the treatment of prostate cancer. In another VACURG (STUDY II)
study of
men with locally advanced and  metastatic disease, 1 mg of
diethylstilbestrol (DES) was slightly more effective than a toxic dose
of
5 mg or a dose of 0.2 mg or a placebo. In a reanalysis of the
VACURG data, a subset of younger men with earlier stages of prostate
cancer
when hormonally suppressed experienced a survival advantage(1).

Similarly, The Medical Research Council Prostate Cancer Working Party
Investigators Group study(2) revealed a survival advantage to early
hormone
suppression for locally advanced disease. The effects of immediate vs
deferred therapy was evaluated in 987 asymptomatic patients in either
Stage
D2 or Stage C (T3) prostate cancer. Patients treated early exhibited
a
marked decrease in comorbid events, such as pathologic fractures,
spinal
cord compression, ureteral obstruction and extraskeletal metastases.

Those on delayed therapy had twice the incidence of these events. The
reduction in these disease related events is enough evidence to
justify the
use of early  therapy. However, additional support for early therapy
comes
from survival data. Patients treated with early therapy exhibited a
small but
significant increase in rates of both overall survival and prostate
cancer-specific
survival. In patients with locally advanced non metastatic disease,
the
benefit was even more pronounced. The survival benefit increased over
time;
the survival rate at 10 years of patients receiving early therapy was
almost
twice that of patients receiving delayed therapy. This study clearly
demonstrates that the earlier the stage of the disease, the less
tumor
burden at the initiation of therapy the better the results. This was
a
controlled randomized clinical  trial.

Another example of the potential benefit of early hormone suppression
versus
delayed we have the Messing EM et al study(3) in which immediate
androgen
deprivation after RP with positive lymph nodes resulted in a survival
advantage for those treated early. At last follow up (median of 7.1
years)
77% of those treated early were alive as compared to 18% in the
delayed
group. As far as cause of death, 6.4% (3/47) patients died of PCa. In
the
delayed group, 31% (16/51)  died of PCa. These are significant
numbers
that support early versus delayed suppression. The recent update
published in 2006 and ignored by Dr Walsh is still very supportive of
early suppression.

Bolla M et al,(4) provided documentation that the combination of
hormonal
therapy and radiation therapy is superior to radiation alone in the
management of T3 prostate cancer. In the Bolla study, 3 years of
hormonal
therapy in combination with 6-7 weeks of external beam radiation
therapy
(EBRT) resulted in a significant therapeutic benefit over radiation
therapy
alone. Estimates of survival after 5 years were greater following
combined
therapy vs EBRT (79% vs 62%). Furthermore, 85% of patients receiving
combined therapy remained disease free, compared with 48% of patients
receiving EBRT alone.

Some have questioned whether radiation therapy contributed
significantly to
the outcome and whether it is clinically necessary. There is
nevertheless a
study done at M.D. Anderson that seems to answer this question. Sagars
GK et
al (5), showed that therapy with androgen deprivation treated patients
had
58% failure rate at 5 years while those on combined therapy (RT + HT)
had a
10% failure rate. This is not a randomized trial but it nevertheless
supports the synergistic value of hormone suppression with radiation
therapy.

Recently D'Amico and coworkers (8) confirmed the synergistic value of
androgen deprivation added to radiation treatment. This study reduced
the
deprivation period to six months and still obtained  an overall
survival benefit .

Another randomized control trial that supports the benefit of
adjuvant
hormone suppression with RT is the Phase III RTOG Protocol 85-31(6).
In this
trial there was 84% of the combined arm showing no evidence of
recurrence
versus 71% in the RT arm at 5 years. More significant, the real
benefit was
in patients with more aggressive disease (Gleason 8 to 10) in which at
the
5-year mark, 66% on the combined arm survived versus 55% in the RT
arm.

In 1998, Granfors et al., reported the results of a controlled trial
in
which 91 patients with surgically confirmed lymph node staged disease
were
randomized to orchiectomy plus radiotherapy and radiotherapy alone.
Those
patients on the RT alone arm that progressed were then treated with
androgen
deprivation. Clinical progression was observed in 61% of those treated
with
RT alone and in 31% in those on combined treatment. Mortality was 61%
and
38% respectively. Disease-specific mortality was 44% with RT and 27%
in the
combined therapy group. Negative lymph node patients showed no
significant
difference in survival. These results suggests that early androgen
suppression is better than delayed hormone suppression treatment  for
these
patients

The value of early hormone suppression is not clear-cut, absolute or
proven case by these randomized clinical trials mentioned above, but
the
existing evidence should not be ignored and physicians that project a
pessimistic stance to their patients need to revisit the latest
medical
literature and get back on track for the benefit of their patients.
Why is then Dr. Walsh ignoring these results?

Why would anyone advise men with advanced disease to postpone
hormone suppression until they become less responsive is hard to
understand, but this is what  happens in many instances. Men need to
realize that the there is a new paradigm for prostate cancer in the
PSA era.
Men should not allow a physician or layman confuse them on this
issue.
Don't allow an old myth to detract from your quality and extension of
life if
YOU DECIDE to be treated as early as possible.

RalphV
www.pcainaz.org/phpbb

Sources:
(1) Byar DP, et al. NCI Monograph 7. 1988;165-170.

(2) Immediate versus deferred treatment for advanced prostatic
cancer:
initial results of the Medical Research Council Trial. The Medical
Research
Council Prostate Cancer Working Party Investigators Group. Br J Urol
1997
Feb;79(2):235-46

(3) Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D.
Immediate hormonal therapy compared with observation after radical
prostatectomy and pelvic lymphadenectomy in men with node-positive
prostate
cancer. N Engl J Med. 1999;341(24):1781-1788.

(4) Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients
with
locally advanced prostate cancer treated with radiotherapy and
goserelin. N
Engl J Med. 1997;337:295-300.

(5) Zagars GK et al., Management of unfavorable locoregional prostate
carcinoma with radiation and androgen ablation. Cancer 1997 Aug
15;80(4):764-775

(6) Pilepich MV et al., Phase III trial of androgen suppression using
goserelin in unfavorable-prognosis carcinoma of the prostate treated
with
definitive radiotherapy: report of Radiation Therapy Oncology Group
Protocol
85-31. J Clin Oncol. 1997; 15: 1013  1021.

(7) 1: Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R,
Dorr
FA, Blumenstein BA, Davis MA, Goodman PJ. A controlled trial of
leuprolide
with and without flutamide in prostatic carcinoma. N Engl J Med. 1989
Aug
17;321(7):419-24. PMID: 2503724 [PubMed - indexed for MEDLINE]

(8) D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A,
Kantoff PW.
6-month androgen suppression plus radiation therapy vs radiation
therapy alone
for patients with clinically localized prostate cancer: a randomized
controlled
trial. JAMA.  2004 Aug 18;292(7):821-7.

(9)Labrie F, Dupont A, Cusan L, Gomez JL, Diamond P.
Major advantages of "early" administration of endocrine combination
therapy in
advanced prostate cancer. Clin Invest Med.  1993 Dec;16(6):493-8.

(10) AARON J. MILBANK, ROBERT DREICER, AND ERIC A. KLEIN. HORMONAL
THERAPY FOR PROSTATE CANCER: PRIMUM NON NOCERE
UROLOGY 60: 738-741, 2002

Other supportive references:

Kozlowski JM, Ellis WJ, Grayhack JT Advanced prostatic carcinoma.
Early
versus late endocrine therapy. Urol Clin North Am 1991 Feb;18(1):
15-24

Mazeman E, Bertrand P. Early versus delayed hormonal therapy in
advanced
prostate cancer. Eur Urol. 1996;30 Suppl 1:40-3; discussion 49.
Review.
PMID: 9072496 [PubMed - indexed for MEDLINE]

Anderson JB. Early versus deferred hormone therapy. Eur Urol. 1999;36
Suppl
2:9-13. PMID: 10529560 [PubMed - indexed for MEDLI