CRPC & Transdermal Estrogen

[pjoshea13]

New to PubMed, below [1].

British, but seemingly unrelated to the estradiol PATCH trial.

"This study was carried out to determine the safety and effectiveness of transdermal estrogens in CRPC." {Although note the later use of DES.} This was a dose-escalation study. "A starting dose of 50 mcg/24 hours was applied and increased if prostate-specific antigen (PSA) rose > 5 ng/mL in steps to 300 mcg/24 hours."

"Five (13%) of 40 patients had > 50% PSA reduction for at least 1 month at any transdermal estradiol dose."

Note: "Patients who progressed were offered diethylstilbestrol." [DES] "Fifty percent of patients subsequently responded to low-dose diethylstilbestrol."

DES, of course, is the synthetic estrogen that was standard for 30-40 years before Lupron. The mechanism of action that causes testosterone to fall is the same as with estradiol, but DES seems to have additional properties. There have been studies that show some response to DES after Lupron, etc, failure.

The doses of (oral) DES used before Lupron became available 35 years ago were high (5mg or more daily) & often resulted in coagulation events. The modern approach is to use the lowest dose that works - often 1mg.

OK, so some CRPC men respond, to estradiol, DES and testosterone too, but I have never seen a discussion as to the characteristics of tumors that respond, or the altered characteristics of cells after the response ends. Or the possibility of the cancer having been resensitized to prior therapies.

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/321...

Clin Genitourin Cancer

2019 Oct 10[Online ahead of print]

The Use of Transdermal Estrogen in Castrate-resistant, Steroid-refractory Prostate Cancer

Katherine Smith 1 , Myria Galazi 1 , Mark R Openshaw 2 , Peter Wilson 1 , Shah J Sarker 3 , Neale O'Brien 1 , Constantine Alifrangis 1 , Justin Stebbing 2 , Jonathan Shamash 4

Affiliations expand

PMID: 32171601 DOI: 10.1016/j.clgc.2019.09.019

Abstract

Background: Androgen-deprivation therapy is the mainstay of treatment for metastatic prostate cancer. Corticosteroids and estrogens are also useful agents in castration-resistant prostate cancer (CRPC). However, oral estrogens are associated with thromboembolic events, which limits their use, and transdermal estrogens may offer a safer alternative. This study was carried out to determine the safety and effectiveness of transdermal estrogens in CRPC.

Patients and methods: Forty-one patients with CRPC and steroid-resistant prostate cancer were eligible for this dose-escalation study of transdermal estradiol. A starting dose of 50 mcg/24 hours was applied and increased if prostate-specific antigen (PSA) rose > 5 ng/mL in steps to 300 mcg/24 hours. The primary endpoint was PSA response, and secondary outcomes included incidence of thromboembolic events and progression-free survival. Patients who progressed were offered diethylstilbestrol.

Results: Five (13%) of 40 patients had > 50% PSA reduction for at least 1 month at any transdermal estradiol dose. No venous-thromboembolic events were observed, and responses plateaued at 200 mcg/24 hours. A correlation between PSA response and rising sex hormone binding globulin was seen. Fifty percent of patients subsequently responded to low-dose diethylstilbestrol.

Conclusion: Transdermal estradiol appears to be a low toxicity treatment option to control CRPC after failure of steroid therapy. Modulation of sex hormone binding globulin by transdermal estradiol may be one mechanism of action of estrogens on CRPC. Oral estrogens remain effective after the use of transdermal estradiol.

Keywords: Diethylstilbestrol; Dose escalation; PSA; Sex hormone binding globulin; Transdermal estradiol.

Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.

[MateoBeach]

Estradiol causes feedback inhibition of LHRH when in sufficient dosage (levels). So that final pathway is the same as for LHRH agonists (Lupron) and antagonist (firmagon) and similar. This can be verified by measuring Testosterone levels to confirm castrate (<20) status. (Regardless of changes in sex-hormone binding globulin effects notwithstanding. )

FSH and LH levels can also be monitored.

The PATCH Trial modified their starting dosage to the equivalent of 4 patches worn at a time of the 0.10 mg/24 hrs biweekly patches with one patch changed daily on a rotating basis. (Note that most, about 2/3, varying by brand, of the Estradiol is actually absorbed in the first 48 hrs after application and not evenly for 4 days.)

The presence of estradiol during ADT helps support improved bone mineralization and controls hot flashes. My own experience is also less mental "fogginess".

PSA must be regularly monitored for effectiveness as in some advanced PCs estrogen can become a stimulator of growth. This will be demonstrated in accelerated PSA rise, indicating time to stop it.

MY experience with Patches for ADT showed that the onset was rather slow, taking over a month to approach castrate T level. So one could consider a single dose of degarelix to rapidly produce a castrate level of ADT and then let the Estradiol Patches take over.

[PhilipSZacarias in reply to MateoBeach]

Excellent response! Cheers, Phil