On June 14, Bill replied to me:

Quoting me:

He wrote:

If that assumption is correct, then it's their problem, not mine.

I did not quote the entire article, of course. One who reads it should
achieve a full understanding of Strum's position.

True, and not news.

Oh? Then why treat them at all? I respect Bill's opinions, but I'm
afraid that he has misspoken (or is it miswritten?).

Bill is correct, as far as he goes. But is that the purpose of ADT? Or
is its purpose to debulk the tumor and, later, to control proliferation
(yes, of androgen-sensitive cells, true enough). And with regard to
direct influence on survival,  absence of proof is not proof of absence.

"....ADT was not associated with significantly increased survival
benefit for older men with locoregional CaP."
See Holmes L, et al., "Effectiveness of androgen deprivation therapy in
prolonging survival
of older men treated for locoregional prostate cancer." Prostate Cancer
Prostatic Dis. 2007 May 8 Pub Med ID 17486111. The study covered
diagnoses in 1992-1999, with the last followup in 2002.

I understand that there are studies now in progress re: adjuvant ADT and
its possible enhancement of the primary tx's effectiveness. Although it
is anecdotal, I can say that it helped this extensive Gleason-9 patient.
So far....

Nor was I.

Not contra Strum. "Patients were followed off therapy and advised to
restart ADT if the PSA level reached > or = 5.0 ng/ml." See, Strum SB,
et al., "Intermittent androgen deprivation in prostate cancer patients:
factors predictive of prolonged time off therapy."  Oncologist.
2000;5(1):45-52. Pub Med http://tinyurl.com/2u8uby
Pub Med ID 10706649.

I am unsure whether Bill has had a previous regimen of ADT. So perhaps
the above would not apply to his case, though I don't see why it wouldn't.

I wonder whether Strum would say the same today. It does not seem to me
to be prudent. Here's what he had to say in a recent P2P post: ""There
is NOWHERE in oncology where waiting for the tumor cell population to
increase (and to mutate) is in the better interests of the  patient."
(emphasis in original)

Reducing the tumor burden via ADT is widely practiced. The
numbers-crunchers have yet to pronounce upon its effectiveness in terms
of survival, true enough. Intuitively, though, I think that it can't
hurt and might help. Pretty much like off-label use of Proscar or
Avodart to control metabolism of T into DHT (dihydrotestosterone).

Regards,

Steve J

Bill,
Although androgen independent cells exist in the prostate gland as
part of its composition(stem cells) they are in the minority. The bulk
of the prostate gland is made of androgen dependent epithelial cells.
Androgen-independence is a process by which the majority of androgen
dependent cells develop (by various mechanisms) the potential of
surviving even when deprived of androgen. It makes sense to avoid this
process as much as possible since hormone resistance is an end step in
disease progression for which cure at this point in time is not
available.

Although the evidence supports early before delayed suppression,
still each patient must decide his own preferences. What follows is
something written some time ago, but still currently valid:

Early versus delayed hormonal suppression ... the evidence for early
treatment.
Hormonal suppression has been the mainstay of treatment for advanced
forms of prostate cancer. Although early clinical studies suggested
that major improvements and even sporadic cure could occur, later
randomized prospective investigations showed that hormonal treatments
were palliative rather than curative. The real question then became
one of comparing quality of life issues with a survival potential in
utilizing hormonal suppression as early or delayed treatment.

As a result of the data generated by Veterans Administration
Cooperative Urologic Research Group showing high toxicity in patients
treated with estrogen therapy, delayed hormonal suppression has been
accepted as standard practice. Reanalysis of those data using cancer-
specific deaths showed improved cancer-specific survival with early
hormonal therapy in selected patients diagnosed with early stages of
advanced disease. A large and growing body of clinical data now
suggests a superior benefit to early hormonal therapy.(18,19) Aside
from the survival benefit, it is now well established that early
hormonal treatment significantly delays the onset of disease
progression, which may correlate with an improved quality of life.(20,
21)

In a randomized study by the U.K. Medical Research Council Prostate
Cancer Working Party Investigators Group, results demonstrated a 32%
survival benefit with early hormonal suppression over delayed
suppression, and at the same time pathological fracture, spinal cord
compression, ureteric obstruction and development of extra-skeletal
metastases were twice as common in deferred patients.(22)    Improving
quality of life is thus an important issue in applying hormonal
suppression at an early stage of advanced disease.

In another randomized clinical trial, Messing EM and co-workers,(23)
compared immediate and delayed treatment in patients who had minimal
residual disease after radical prostatectomy. RESULTS: After a median
of 7.1 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). The cause of death was prostate cancer in
3 men in the immediate-treatment group and in 16 men in the
observation group (P<0.01) and the researchers concluded: Immediate
antiandrogen therapy after radical prostatectomy and pelvic
lymphadenectomy improves survival and reduces the risk of recurrence
in patients with node-positive prostate cancer.

Granfors et al(28) reported the results of 91 patients with clinically
localized prostate cancer who were treated for pelvic-confined
prostate cancer. Patients had surgical lymph node staging and were
then randomized to receive definitive external-beam radiotherapy or
combined orchiectomy and radiotherapy. Patients who received radiation
alone without hormonal treatment were treated with androgen ablation
at clinical evidence of disease progression. Results were reported at
a median follow-up of 9.3 years. Clinical progression was observed in
61% of patients treated with radiotherapy alone and in 31% of patients
who received combined treatment (P=.005). Mortality was 61% and 38%,
respectively, and cause-specific mortality was 44% and 27%,
respectively (P=.06), in groups 1 and 2. Differences in favor of
combined treatment were mainly seen in lymph node positive tumors.
Node-negative tumors showed no significant difference in survival
rates. The authors concluded the progression-free, disease-specific,
and overall survival rates for patients with prostate cancer and
pelvic lymph node involvement are significantly better after combined
androgen ablation and radiotherapy than after radiotherapy alone.
These results strongly suggest that early androgen deprivation is
better than deferred endocrine treatment for these patients(28)

Bolla et al(29) reported results of 415 patients with locally advanced
prostate cancer. Patients were randomized to receive radiation therapy
alone or radiotherapy plus immediate treatment with goserelin for 3
years. The median follow-up was 45 months. Kaplan-Meier estimates of
overall survival at 5 years were 79% in the combined-treatment group
and 62% in the radiotherapy group (P=.001). The proportion of
surviving patients who were free of disease at 5 years was 85% in the
combined-treatment group and 48% in the radiotherapy-alone group (P<.
001). The authors concluded adjuvant treatment with goserelin when
started simultaneously with external-beam radiation improved local
control and survival in patients who had locally advanced prostate
cancer.

For many years, there has been published evidence that demonstrates
that the lower the tumor burden the better the response to hormone
suppression. This was clearly demonstrated by Crawford ED et al(24) in
1989. In this study, men were stratified by the degree of their cancer
progression at diagnosis. The response to combined suppression was as
follows:

1. Advanced disease with major symptoms such as bone pain, weight loss
etc. responded
for only 8.5 months.
2. Advanced disease with minor symptoms, responded for 15.4 months.
3. Advanced disease limited to lymph nodes, responded for 4 years.

In this study done more than a dozen years ago, 10% of the patients in
the No. 1 category were still responding after 4 years while 35% of
the patients with disease limited to lymph nodes were still responding
after 10 years. This is a clear indication that hormonal response is
directly proportional to the degree of disease progression at the time
of diagnosis and that each patient's disease can elicit a different
response to treatment.

RalphV
pcainaz.org/phpbb

References
18. Cookson MS, Sarosdy MF Hormonal therapy for metastatic prostate
cancer: issues of timing and total androgen ablation. South Med J 1994
Jan;87(1):1-6
19. Kozlowski JM, Ellis WJ, Grayhack JT Advanced prostatic carcinoma.
Early versus late endocrine therapy. Urol Clin North Am 1991 Feb;18(1):
15-24
20. Mazeman E, Bertrand P Early versus delayed hormonal therapy in
advanced prostate cancer. Eur Urol 1996;30 Suppl 1:40-43
21. Kramolowsky EV The value of testosterone deprivation in stage D1
carcinoma of the prostate. J Urol 1988 Jun;139(6):1242-1244
22. 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
23. Messing EM Immediate hormonal therapy compared with observation
after radical prostatectomy and pelvic lymphadenectomy in men with
node-positive prostate cancer.
N Engl J Med 1999 Dec 9;341(24):1781-8

24. 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.
28. Granfors T, Modig H, Damber JE, et al. Combined orchiectomy and
external radiotherapy versus radiotherapy alone for nonmetastatic
prostate cancer with or without pelvic lymph node involvement: a
prospective randomized study. J Urol. 1998;159: 2030-2034.
29.  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.