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Click Here to Return to Proven Treatments DES and Estrogens for HRPC April 2, 2002
Introduction | How it is Thought to Work | Suggested Dose Options Side Effects and Prevention | Summary of Studies | References
Estrogen use for advanced prostate cancer dates back to the 1940s and it worked effectively as a version of androgen deprivation therapy. In the form of DES(diethylstilbestrol), doses of 5mg/day were used, but significant cardiovascular toxicity was noted. The advent of drugs such as the LH-RH agonists and concern with the side effects, led to the decline in its use. For the treatment of prostate cancer, it has been called the "Forgotten Drug"(1). Today, the drug is only available in the USA from "compounding" pharmacies. A resurgence of interest in it, however, is occurring as it has demonstrated use for hrpc as a secondary hormonal manipulation. Myers(2) says, "DES is not a true estrogen, but a chemical that happens to mimic estrogen in the blood stream. The chemical structure of DES is similar to the chemical stilbene. This same chemical structure was also used to produce the anti-estrogen drug, tamoxifene." TACE is another synthetic estrogenic drug with the similarity to stilbene and it can be used as a replacement for DES. It is said to have the same side effect profile as DES. DES is a non-steroidal estrogen(synthetic) and acts to suppress testosterone. Estrogens go to the brain and reduce the amount of LH(Leutenizing Hormone) that is produced. LH stimulates the testes to produce testosterone, so lower LH means less testosterone. In this respect, it is similar to LH-RH agonists(e.g., Lupron, Zoladex) and thus it has an inhibitory effect on androgen dependent cells. We know it also works in some men who are hrpc. Malkowicz(3) says, that in addition to the suppression of LH, estrogens may also increase the levels of SHBG(sex hormone binding globulin) and increase pituitary prolactin secretion. Data from Kitahara et al(4), suggests that DES may reduce serum dihydroepiandrosterone sulfate, while increasing SHBG and cortisol levels in hrpc. An in vitro study by Robertson et al(5), demonstrated that DES has a direct cytotoxic effect. The cytotoxic effect was attributed to cell cycle control and apoptosis mechanisms. There is an abundance of information indicating that 5 mg is too high a dose given the side effects and that lower doses have similar efficacy against prostate cancer with a lower toxic profile. The 5mg/day dose results in castrate levels of testosterone as does the 3mg/day dose. A dose of 1mg/day is not sufficient to reduce serum testosterone to castrate levels in all patients. However, the 1mg/day and 3mg/day doses have equivalent effects on prostate cancer.(6) Jazieh AR, et al(7) used a dose of 1mg 3x/day along with routine anticoagulation with warfarin (Coumadin). The 14 men in this study were post-orchiectomy with progressive prostate cancer (AIPC)(small sample size). Nine of 14 had PSA declines > 75% from baseline PSA and there were no cardiovascular or thrombotic events reported. Smith, et al(6) found that 1 of the 21 hrpc men in their study with 1 mg DES had a DVT. The choice seems to be 1 mg/day or 1 mg 3x/day. One could start with 1mg/day and if that lowered your PSA continue, if not, increase the dose to 1mg 3x/day. Discuss the options carefully with your doctor and consider anti-coagulation with coumadin.
Side Effects and Prevention(1mg/day to 3mg/day only)
The review article by Cox and Crawford (8) and the paper by Malkowicz(3) both cover the many possible side effects of estrogen/DES therapy. Malkowicz(3) notes that anywhere from 8% to 12.6% thromboembolic events for 3mg DES were observed and even at 1mg DES/day there can be 8% to 21% cardiovascular side effects. These studies were done without anti-coagulation with coumadin. Klotz et al(9) did a study with 1mg coumadin and 3mg or 2 mg DES with the result that 10 patients (31%) had clinically significant proximal DVT develop. Smith et al(6) in their phase II study of 1mg/day DES(alone) had 1 patient of 21 (5%) develop a DVT. Malkowicz(3) notes that the rate of thromboembolic events when aspirin is used is in the 3%(100mg) to 12%(75mg) range. Finally, note that Jazieh et al(7) did not find any cardiovascular or thrombotic (blood clotting) in their study with 1mg 3x/day and routine coumadin anti-coagulation.
Dr. Stephen Strum(10) advocates anti-coagulating with coumadin to an INR 2-2.5. In a recent post on P2P(10/10/2002) he also stated:
"the use of an estrogen should MANDATE anti-coagulation when the estrogen is given orally. This is because oral use of estrogenic compounds results in AT3 deficiency and this increases the risk of thrombosis. This potential adverse effect is prevented by the use of Coumadin (warfarin). It is not prevented by aspirin."
Pre-treatment of the nipple bud area is also warranted as there is a high incidence of nipple tenderness and breast enlargement(gynecomastia) with estrogen therapy. Strum suggests a 300- 400 cGy/day dose of radiation for 3-4 days prior to starting any estrogenic compound. Malkowicz(3) says that the reported dose has ranged from 6 to 15 Gy and just how effective this is in preventing gynecomastia has not been rigorously documented. With an incidence rate of about 40%, one would not want to ignore this advice and it must be done before developing gynecomastia. Once breast enlargement occurs, it is less likely that radiating the nipple bud area will be effective.
The following table summarizes studies pertaining to anti-coagulation vs no anti-coagulation and thromboembolic events or cardiovascular side effects. Some caution is advised due to the small sample sizes.
Other side effects include high blood pressure and edema. Oral estrogens, in particular, almost entirely must flow through the liver before passing to the rest of the body. The increased estrogen in the liver induces it to release proteins(renin and angiotensin). Renin and angiotensin, then, via the kidney cause retention of salt and water. The extra salt and water can lead to edema and high blood pressure. Lower doses, diuretics and blood thinners can treat these side effects.
Of the many studies, only a few will be listed here. For a more thorough discussion, see the Life Extension Foundations's Protocol Book www.lef.org. The section on abstracts for the use of estrogens can be found at http://www.lef.org/protocols/prtcl-094g.shtml.
Note 1: the best responses in studies have been when DES is used as a second line hormone therapy(i.e., as the 1st therapy following failure of primary androgen ablation). In the phase II study of Smith et al (6), eight of 13 patients (62%) who had only one prior hormone manipulation that failed demonstrated a PSA response, but whereas only 1 of 8 patients (13%) who had received two or more hormone treatments responded(50% drop in PSA).
Note 2: The response rate was 100% for men having had total androgen blockade alone; 45% in men who had additionally been treated with aminoglutetamide + hydrocortisone and it was 50% in men who had total androgen blockade and chemo. 1. "DES: The Forgotten Drug," PCRI Insights Newsletter, October 1998 Volume 1, No. 1, page 9. See www.prostate-cancer.org and click on Insights Newsletter.
2. Myers, CM, New Thoughts on the Use of Estrogens to Treat Prostate Cancer, US TOO Prostate Cancer Communicator Article, Volume No. 1, Issue No. 7 (July – December, 1997).
3. Malkowicz SB, The role of diethylstilbestrol in the treatment of prostate cancer. Urology 2001 Aug;58(2 Suppl 1):108-13, Division of Urology, Department of Surgery, University of Pennsylvania Medical Center, Philadelphia Pennsylvania, USA.
4. Kitahara S, Umeda H, Yano M, et al: Effects of intravenous administration of high dose diethylstilbestrol diphosphonate on serum hormonal levels in patients with hormone refractory prostate cancer. Endocr J 4: 659-664, 1999.
5. Robertson C, Roberson K, Padilla G, et al: Induction of apoptosis by diethylstilbestrol in hormone-insensitive prostate cancer cells. J Natl Cancer Inst II: 917-926, 1996.
6. Smith DC, Redman BG, Flaherty LE et al: A Phase II Trial of Oral DES as a second-line Hormonal Agent in Advanced Prostate Cancer, Urology, volume 52 (2), 1998, pp. 257-260.
7. Jazieh AR, Munshi NC, Muirhead M, et al: Clinical efficacy of Diethylstilbestrol treatment in post-orchiectomy progressive prostate cancer. Proc AACR, 35:233, 1994.
8. Cox RL and Crawford DE: Estrogens in the Treatment of Prostate Cancer, J. of Urology, Vol. 54, pp. 1991-1998, December 1995.
9. Klotz L, McNeill I, Fleshner N., A phase 1-2 trial of diethylstilbestrol plus low dose warfarin in advanced prostate carcinoma. J Urol 1999 Jan;161(1):169-72.
10. Stephen Strum, MD, Prostate Cancer Research Institute, Prescription Drug Alternatives to PC Spes.
11. M Shahidi, A R Norman, J Gadd, J Simpson, R A Huddart, A Horwich, D P Dearnaley, The Institute of Cancer Research and The Royal Marsden NHS Trust, Sutton, UK., Prospective Review of Diethylstilbestrol in Advanced Prostate Cancer No Longer Responding to Androgen Suppression. ASCO 2001 Abstract #2455.
12. Rosenbaum E, Wygoda M, Gips M, et al: Diethylstilbestrol is an active agent in prostate cancer patients after failure to complete androgen blockade[ASCO 2000 abstract #1372]. J Clin Oncol 349a.
Other ESTROGENS Much of what has been said above for DES applies to natural estrogens or other estrogens which will be discussed here.
Natural estrogen options are summarized in the table below. The quantities listed below are from various sources. Your own physician will have to determine what is appropriate for you.
(a) See http://www.climara-us.com (b) See http://www.pharma.us.novartis.com/product/pi/pdf/estraderm.pdf (c) fosfestrol goes by the names of honvan, fosfostilben, honvol and ST-52(European formulation).
Orlando et al(1), in a study of 38 patients, using fosfestrol had a PSA response rate of 79%, with a duration of response of 7 months. Fosfestrol is a prodrug that is metabolized to DES in the cancer cells.
Another excellent discussions of estrogens is found in (2) and (3).
References
1. Orlando M, Chacon M, Salum G, Chaco Dr. Low-dose continuous fosfestrol is highly active in hormone-refractory prostate cancer. Ann Oncol 11:177-181, 2000.
2. Myers, CM, New Thoughts on the Use of Estrogens to Treat Prostate Cancer, US TOO Prostate Cancer Communicator Article, Volume No. 1, Issue No. 7 (July – December, 1997).
3. See the Life Extension Foundations's Protocol Book www.lef.org. The section on abstracts for the use of estrogens can be found at http://www.lef.org/protocols/prtcl-094g.shtml.
Another possible side effect of estrogen administration is the elevation of prolactin levels. It has been suggested by at least one physician that lowering prolactin levels to <1 could be beneficial. The drug dostinex, taken .5mg on Mondays and Thursdays is one way of lowering prolactin levels. Consult your physician.
An intriguing item, mentioned in Small EJ and Vogelzang, NJ (JCO 1997 Jan:15(1):383-8) is that after failing anti-androgen and failure of estrogen therapy, a reponse can be had again with anti-androgens. This is attributed to redifferentiation of cancer cells by mutation of the androgen receptors.
Another area for study involves anti-estrogens. Responses due to tamoxifen have been seen, although the response rate is small(see Bergan, RC, et al, Proc. Amer. Soc Clin. Oncol, 14:A637, 1995, Significant activity by high dose tamoxifen in hrpca. 5 of 13 partial responses by PSA criteria). See also, Horton et al, Tamoxifen in advanced prostate cancer: an ECOG pilot study. Prostate, 12:173, 1988 (0-10% measurable response). Raloxifene(Evista) may fit into this category also.
Author: Howard Hansen Comments and suggestions for additions and changes in this writeup are requested. |
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