Androgen deprivation is not innocuous therapy and a decision to use it now or later needs careful consideration. One should not ignore the fact that the longer prostate cancer progresses naturally the more it inexorably advances to an androgen independent state on its own. Given enough time and growth factors the endpoint of untreated prostate cancer is androgen independence. These are known biological facts.
Some 20% of untreated advanced prostate cancer patients do not respond to androgen suppression. This implies that on its own the disease has become androgen independent BEFORE the disease is diagnosed or androgen deprivation is initiated.
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 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 20 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 allow androgen dependent cells to become androgen independent when they could be killed by androgen deprivation applied early 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 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 multiple 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.
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.
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
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.
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.
We constantly hear, and rightly so, about the side effects of treatment.
We all need to know them in detail to be able to deal with them.
Do we ever hear about the symptoms and loss of quality of life
from untreated or untimely treatment in disease progression? Is allowing the cancer to invade the bone or organs inconsequential? Those who understand this dichotomy need to recognize that timely treatment/no treatment decisions can impact their lives in a significant way…to ignore it is far from reality.
(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
(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
(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 MEDLINE]
Surviving prostate cancer since 1992 at age 58. RP; Orchiectomy; GS (4 + 2); bilateral seminal vesicle invasion; tumor attached to rectal wall; Stage T4; Last PSA September, 2010: <0.1 ng/ml
Laughter is still the best medicine!