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

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.

Full text

Transdermal*oestrogen*in*prostate*cancer*
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The$use$of$Transdermal$Oestrogen$in$Castrate-
resistant,$Steroid-refractory$Prostate$Cancer$
Smith$K.1,$Galazi$M1,$Openshaw$M.$R.2*,$Wilson$P.1,$Sarker$S.$J.3,$O’Brein$N.1,$Alifrangis$
C1,$Stebbing$J.2$$and$Shamash$J1$
1Barts$Cancer$Institute,$Saint$Bartholomew’s$Hospital,$London,$UK$
2$ Department$ of$ Medical$ Oncology,$ Charing$ Cross$ Hospital,$ Imperial$ College$ NHS$
Trust,$London,$UK$
3Centre$ for$ Experimental$ Cancer$ Medicine,$ Queen$ Mary$ $ University$ of$ London,$
London,$UK$
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Corresponding$author:$
$
Dr$Jonathan$Shamash$
jonathan.shamash@bartshealth.nhs.uk$
Department$of$Medical$Oncology,$St$Bartholomew’s$Hospital,$West$Smithfield,$EC1A$
7BE,$UK$
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CTA$number$14620/0013/001$
Protocol$number$PR-2004-04$issued$by$MHRA$
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Key$ Words:$ Castrate$ resistant$ prostate$ cancer,$ transdermal$ oestradiol,$
diethylstilbestrol,$PSA$
*Manuscript
Click here to download Manuscript: oestradiol paper_with revisions.pdf

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Microabstract$
We$ aimed$ to$ investigate$ the$ role$ and$ safety$ of$ transdermal$ oestrogen$ therapy$ in$
castrate$ resistant$ prostate$ cancer.$Within$ this$ dose$ escalation$ study$we$ observed$
reduction$ in$ PSA$ levels$ at$ all$ doses$ used.$ In$ addition,$no$ venous$ thromboembolic$
events$ were$ detected$ making$ the$ use$ of$ transdermal$ oestradiol$ a$ safe$ treatment$
option$for$a$subgroup$of$patients$with$castration-resistant$prostate$cancer.$
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Abstract$
Background:$ Androgen-deprivation$ therapy$ is$the$ mainstay$ of$ treatment$for$
metastatic$prostate$ cancer.$Corticosteroids$and$oestrogens$are$also$useful$agents$in$
castrate$ resistant$ prostate$cancer.$ However,$ oral$ oestrogens$ are$ associated$ with$
thromboembolic$events,$which$limits$their$use$and$transdermal$oestrogens$may$offer$
a$ safer$ alternative.$This$ study$ was$ carried$ out$ to$determine$ the$ safety$ and$
effectiveness$of$transdermal$oestrogens$in$castrate$resistant$prostate$cancer.$
Patients$and$ Methods:$41$ patients$ with$ castration$ and$ steroid-resistant$ prostate$
cancer$ were$ eligible$ for$ this$ dose-escalation$ study$ of$ transdermal$ oestradiol.$ A$
starting$ dose$ of$ 50mcg/24$ hours$ was$ applied$ and$ increased$ if$ PSA$ rose$ >5ng/ml$ in$
steps$ to$ 300mcg/24hours.$ 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:$5/40$ patients$ (13%)$ had$ >50%$ PSA$ reduction$ for$ at$ least$ 1$ month$ at$ any$
transdermal$oestradiol$dose.$No$venous-thromboembolic$events$were$observed$and$
responses$ plateaued$at$ 200mcg/24hours.$ A$ correlation$ between$ PSA$ response$ and$
rising$ sex$ hormone$ binding$ globulin$was$ seen.$ 50%$ of$ patients$subsequently$
responded$to$low$dose$diethylstilbestrol.$
Conclusion:$Transdermal$oestradiol$appears$to$be$a$low$toxicity$treatment$option$to$
control$ CRPC$after$ failure$ of$ steroid$ therapy.$ Modulation$ of$ sex$ hormone$ binding$

Transdermal*oestrogen*in*prostate*cancer*
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globulin$by$transdermal$oestradiol$may$be$one$mechanism$of$action$of$oestrogens$on$
castrate$resistant$prostate$cancer.$Oral$oestrogens$ remain$effective$after$the$use$of$
transdermal$oestradiol.$$
$ $

Transdermal*oestrogen*in*prostate*cancer*
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Abbreviations:$$
TDE$=$Transdermal$oestrogen$
CRPC$=$castrate-resistant$prostate$cancer$
PSA$=$prostate$specific$antigen$
ADT$=$androgen$deprivation$therapy$
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Introduction:$
Prostate$ cancer$ is$ the$ commonest$ cancer$ in$ men$and$ the$ second$ most$ common$
cause$of$cancer-related$death$in$men$in$the$ UK$ (1).$The$disease$exhibits$remarkable$
heterogeneity$in$clinical$behaviour$and$outcome$ranging$from$years$of$indolence$to$
lethal$disease$despite$similar$histological$features$(2).$$Androgen$deprivation$therapy$
(ADT)$is$the$standard$of$care$for$metastatic$prostate$cancer$and$it$also$has$a$role$in$
the$ neoadjuvant$ and$ adjuvant$ settings.$ Initial$ response$ rates$ to$ ADT$ exceed$ 80%,$
however$these$are$transient$and$patients$invariably$progress$to$the$more$aggressive$
phenotype$of$ the$ disease$ termed$ castration-resistant$ prostate$ cancer$ or$ CRPC$ (3).$
ADT$is$ most$ often$ achieved$ by$ administration$ of$ gonadotropin-releasing$ hormone$
(GnRH)$ analogues$(4).$ Their$ use$ is$associated$ with$ numerous$ long-term$ toxicities$
including$ hot$ flushes,$ gynaecomastia,$ increased$ cardiovascular$events$ and$ reduced$
bone$mineral$density$(4-6).$
Even$ at$ the$ time$ of$ development$ of$ resistance$ to$ ADT,$ research$ has$ demonstrated$
that$androgen$receptor$(AR)$signaling$remains$crucial$for$the$progression$of$CRPC.$As$
a$ result,$ potent$ second$ generation$ anti-androgen$ drugs$ have$ been$ developed$ that$
target$the$AR$pathway.$More$specifically,$abiraterone$acetate$and$enzalutamide$have$
both$ been$ approved$ for$ use$ in$ the$ pre-$ and$ post-chemotherapy$ settings$ following$
improvements$in$ OS$in$ men$ with$ CRPC$ (7-10).$ Despite$ their$impressive$ responses,$
however,$these$novel$treatments$are$associated$with$ numerous$ toxicities$especially$

Transdermal*oestrogen*in*prostate*cancer*
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within$the$ elderly$prostate$ cancer$ patient$ population$ who$might$not$tolerate$ these$
treatments$well.$Toxicities$include$fatigue,$oedema,$hypertension$and$diarrhea.$As$a$
result,$ there$ has$ been$ a$ renewed$ interest$ in$ oestrogen$therapy,$ particularly$ for$
patients$who$are$less$fit$with$relatively$low$volume$disease$and$where$chemotherapy$
and$ second$ generation$ anti-androgens$ may$ result$ in$ significant$ toxicity$ with$
associated$effects$on$quality$of$life.$
$
Oral$oestrogen,$ in$ particular$ Diethylstilbestrol$ (DES),$ is$ an$alternative$ agent$used$ to$
induce$medical$castration$(11),$and$prior$to$the$development$of$GnRH$analogues$was$
the$ mainstay$ of$ treatment.$ $ Oestrogen$ decreases$ testosterone$ concentration$ in$
serum$by$suppressing$LH$ production$ from$the$pituitary$via$negative$feedback.$Their$
use$ however,$ was$ abandoned$ due$ to$ their$ association$ with$ venous$
thromboembolism$ (VTE)$ and$ cardiovascular$ toxicity$ (12,$ 13).$ This$ VTE$ risk$ is$
attributed$to$the$effects$of$first$pass$hepatic$metabolism$of$oestrogen$on$coagulation$
proteins$ and$ lipids$ (14).$ Since$ the$ development$ of$ ADT$ using$ GnRH$ analogues,$ the$
main$ use$ of$ DES$ has$ been$ as$ second,$ third$ or$ consecutive$ line$ hormonal$
manipulation.$$$
$
Parenteral$ oestrogens$ have$ been$ shown$ to$ avoid$ first-pass$ metabolism$ in$ the$ liver$
and$ are$ therefore$ not$ expected$ to$ be$ associated$ with$ the$ same$ frequency$ of$

Transdermal*oestrogen*in*prostate*cancer*
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thromboembolic$ events$ as$oral$ oestrogens$ (14).$ Langley$ et$ al$conducted$ a$
randomized$trial$ of$ GnRH$ analogues$ versus$ transdermal$ oestrogen$ (TDE)$ in$
treatment$naïve$locally$advanced$and$metastatic$prostate$cancer$(15).$ TDE$achieved$
equivalent$levels$ of$ castrate$ testosterone$ concentrations$and$ had$similar$ frequency$
of$VTE$complications.$Rates$of$cardiovascular$toxic$effects$were$similar$with$the$two$
treatments$and$were$lower$than$those$seen$with$oral$oestrogen.$As$TDE$may$achieve$
castrate$ levels$ of$ testosterone$ with$ fewer$ cardiovascular$ and$ vascular$thrombotic$
events$it$has$also$been$trialed$in$CRPC.$Furthermore,$PSA$response$rates$have$been$
seen$in$Phase$II$studies$using$TDE$with$no$increases$in$ VTE$or$cardiovascular$events$
(16).$ Response$ rates$ have$ also$ been$ demonstrated$ in$ chemo-refractory$ prostate$
cancer$(17).$However,$the$long-term$efficacy$of$TDE$versus$DES$is$not$known.$$
$
This$dose-escalation$study$of$TDE$was$therefore$designed$to$assess$the$effectiveness$
of$ TDE$ in$ castrate$ resistant$and$ steroid$ refractory$ advanced$ prostate$ cancer$in$
patients$ who$ had$ declined$ or$ felt$ to$ be$ inappropriate$ for$ chemotherapy.$ Patients$
who$came$ off$ study$ were$ offered$ DES$ to$ establish$ if$ there$ is$any$ cross-resistance$
between$TDE$and$DES.$$PSA$was$used$as$a$marker$for$response.$
$
$ $

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Materials$and$Methods$
Patients$
Eligibility$ criteria$ included$ patients$ with$ confirmed$ locally$ advanced$ or$ metastatic$
prostate$ cancer$ with$progression$ of$ disease$ to$ both$ GnRH$analogues$ and$ steroid$
therapy$equivalent$ to$dexamethasone$ 2mg$once$ a$day,$ prednisolone$15mg$per$ day$
or$20mg$hydrocortisone$per$day.$Patients$were$required$to$be$biochemically$castrate$
at$baseline$(serum$testosterone$<2nmol/l).$$
Men$ aged$ ³$18$ years$ with$ an$ Eastern$ Co-operative$ Oncology$ Group$(ECOG)$
performance$ status$ ³$3$ were$ eligible.$ Men$ with$ pre-existing$ vascular$ conditions$ or$
history$of$VTE$were$included,$with$the$exception$of$a$cerebrovascular$event$within$3$
months$ prior$ to$ study$ enrolment.$Other$ exclusion$ criteria$ were$ prior$ oestrogen$
therapy$ or$ other$ active$ malignancy$ within$ the$ last$ 3$ years.$ $ Patients$had$ either$
declined$ docetaxel$ chemotherapy$or$ felt$ to$ be$ inappropriate$ candidates$ for$
chemotherapy$given$their$performance$status.$$
Treatment$
Transdermal$ Evorel®$ oestrogen$ patches$ delivering$ 50mcg$ oestradiol/24hours$ were$
given$to$all$patients.$ GnRH$analogues$and$steroids$were$discontinued$at$ the$start$of$
the$ study.$ Patients$ who$ had$ been$ on$ long$ periods$ of$ steroids$ were$ reduced$ to$
maintenance$levels.$All$patients$were$started$on$Aspirin$75mg$daily$unless$previously$

Transdermal*oestrogen*in*prostate*cancer*
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established$ on$ anti-platelet$ therapy.$ All$ patients$ received$ prophylactic$ Ranitidine$
(150mg$twice$daily).$
$
Baseline$ investigations$ included$ a$ chest$ radiograph,$ electrocardiogram$ and$ a$ bone$
scan.$$
$
Blood$tests$included$full$blood$count,$urea$and$electrolytes,$liver$function,$LDH,$PSA,$
testosterone,$LH,$FSH,$SHBG,$and$oestradiol$levels.$PSA$levels$were$checked$every$28$
days.$ A$ rise$ of$ >5μg/l$ triggered$ a$ repeat$ test$ 7-14$ days$ later.$ If$ this$ rise$ was$
confirmed,$ the$ Evorel®$ dose$ was$ increased$ initially$ to$ 100mcg/24$ hours$ then$ to$
200mcg/24hrs$and$finally$to$ 300mcg/24hrs.$At$the$start$of$ each$ course,$weight$and$
ECOG$ performance$ status$ were$ recorded.$ If$ there$ was$ further$ PSA$ progression$ or$
symptomatic$ progression$ at$ any$ point,$ patients$ were$ taken$ off$ the$ transdermal$
patch.$ Patients$ without$ contra-indication$ due$ to$ thrombo-embolism$ were$ offered$
diethylstilbestrol$1mg/day$following$discontinuation$of$TDE.$
$
Patients$ were$ reviewed$ every$ 28$ days$ during$ treatment$ and$ then$ 3-monthly$ for$ 1$
year.$Subsequent$follow-up$was$at$the$treating$clinician’s$discretion.$$
$

Transdermal*oestrogen*in*prostate*cancer*
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Patients$completed$the$European$Organisation$for$Research$and$Treatment$of$Cancer$
QLQ$C-30$ questionnaire$ and$ PR25$ prostate$ specific$ questionnaires$ to$ assess$ quality$
of$life$outcomes.$$
$
All$patients$gave$written$informed$consent$and$the$study$was$approved$by$the$local$
Ethics$ Committee.$ The$ recruitment$ period$ for$ this$ study$ was$ between$ 2004$ and$
2010.$
$
Statistics$
Endpoints$ were$ measured$ on$ an$ intention-to-treat$ principle.$ The$ primary$ endpoint$
was$ PSA$ response$ rate$ as$ defined$ by$ consensus$ criteria$(18).$ Secondary$ endpoints$
were$ incidence$ of$ thromboembolic$ events$ and$ progression$ free$ survival.$ Statistical$
considerations$indicated$that$ an$ open$study$of$14$ patients$ was$ required$ initially$ for$
95%$ chance$ of$ detecting$ at$ least$ one$ PSA$ response$ (>50%$ reduction$ of$ PSA$
maintained$for$one$month).$If$one$response$was$seen$the$trial$size$would$increase$to$
21$and$to$40$if$further$responses$were$seen$(19).$Stata$statistical$software$was$used$
for$all$statistical$analyses.$$
$
$
$ $

Transdermal*oestrogen*in*prostate*cancer*
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Results$
Patients$
In$ this$ two$centre$ study,$ 41$ patients$ were$ enrolled$in$ total.$ One$ patient$ withdrew$
prior$ to$ commencing$ therapy.$ Baseline$ patient$ characteristics$ are$ given$ in$ Table$ 1.$
Median$ age$ at$ enrollment$ was$ 76$years$ (inter$ quartile$ range$ 72-81).$ 26$ patients$
(65%)$ had$ an$ ECOG$ PS$ of$ 0-1,$ and$ 12$ patients$ (30%)$ 2-3.$ Data$ was$ missing$ for$ 2$
patients.$ Prior$ to$ receiving$ Evorel®,$ all$ patients$ had$ received$ GnRH$ analogues$ or$
undergone$bilateral$orchidectomy.$39$ patients$ (97%)$ received$ prior$steroid$therapy;$
1$ individual$had$an$absolute$ contraindication$ to$ steroids$ due$ to$ ongoing$
osteomyelitis.$No$patients$had$received$prior$chemotherapy.$
$
At$baseline,$the$median$PSA$measured$151ng/dl.$35$patients$(88%)$had$evidence$of$
bony$metastases.$All$ patients$ were$biologically-castrate$ except$ for$2$ (with$ elevated$
serum$ testosterone$ 2.2$ and$ 5.7nmol/l).$ These$ 2$ patients$ did$ not$ meet$ eligibility$
criteria$but$were$included$according$to$intention-to-treat$analysis.$Median$time$from$
diagnosis$ to$ development$ of$ castration$ resistant$ disease$ was$ 38$ months$ (inter$
quartile$range$20-67$months).$The$median$time$on$corticosteroids$prior$to$the$study$
was$ 4.5$ months$ (interquartile$ range$ 2.5-7.5$months).$ The$ median$ time$ from$

Transdermal*oestrogen*in*prostate*cancer*
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castration$resistant$disease$to$entry$to$the$study$was$12$months$(inter$quartile$range$
7.2-18$months).$$
$
Castration$was$maintained$in$all$patients$throughout$the$study$with$the$exception$of$
the$patient$with$the$baseline$serum$testosterone$of$5.7nmol/l.$
$
Table$ 1:$Baseline$ characteristics$ of$ patients$ receiving$ transdermal$ estradiol$ at$
treatment$randomisation:$
$
Number$of$patients$
40$
Median$age$(range)$
76$(58-87)$
Median$ time$ from$ castration$ resistance$ to$ starting$ TDE$
(range),$months$
12$(2-32)$
Median$duration$on$dexamethasone$(range),$months$
5$(1-17)$
ECOG$Performance$status$$
$$
0$
7/38$(18%)$
1$
20/38$(53%)$
2$
8/38$(21%)$
3$
2/38$(5%)$
Median$PSA$(ng/dL)$(range)$
151$(25-1386)$
Median$alkaline$phosphatase$level$(range)$
135$(39-2187)$
Median$haemoglobin$level$(g/dL)$(range)$
11.1$(8.3-16.4)$
Gleason$score$at$diagnosis$
$$
<8$
18/40$
8-10$
$
$
$
$
14/40$
NA$
8/40$
$
$
Presence$of$bony$metastases$$
35/40$(88%)$
$
$
Previous$therapy$
$
$
$
$
$
$
GnRH$agonist$
39/40$(98%)$
Bilateral$orchiectomy$
1/40$(3%)$
Steroid$therapy$
39/40$(97%)$
$
$

Transdermal*oestrogen*in*prostate*cancer*
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Toxicity$
After$4$months$on$treatment,$self-reported$gynaecomastia$had$increased$from$4%$to$
58%$(p=0.001),$however$hot$ flushes$ had$reduced$from$ 25%$ to$8%$(p=0.03).$ Nausea$
reporting$increased$from$ 10%$ to$18%$(p=0.05)$ (see$ Table$2).$There$were$no$ venous$
thrombo-embolic$ events.$ There$ was$ one$ vascular$ event$ (retinal$ artery$ occlusion).$
There$ were$ no$ skeletal$ events$ and$ no$ patients$ were$ on$ i.v.$ bisphosphonates$ or$
denosumab$during$the$study.$There$were$no$treatment$related$deaths.$$
$
Table$ 2:$ Symptoms$ reported$ at$ baseline$ and$ after$ 4$ months$ on$ treatment$
(EORTC-QLQ-C30$and$EORTC-QLQ-PR25):$
$
$
$
$
$
$
$
$
$
Oestradiol$and$Sex$Hormone$Binding$Globulin$
Increasing$TDE$dose$resulted$in$increasing$oestradiol$and$SHBG$concentrations$across$
all$ groups$(p<0.001).$By$ the$ end$ of$ treatment$ 39$ patients$ (97.5%)$ went$ onto$
!
At!baseline!
After!4!months!on!study!
!
!
!
Hot!flushes!
(7/28)!25%!
(2/26)!!8%!!!!!!!!!!!!!(p=0.03)!
Gynaecomastia!
(1/28)!4%!
(15/26)!!58%!!!!!!!!(p=0.001)!
Loss!of!masculinity!
(11/28)!39%!
(9/26)!!35%!!!!!!!!!!(p=0.29)!
Insomnia!
(11/31)!35%!
(11/27)!!42%!!!!!!!!(p=0.19)!
Nausea!and!vomiting!
(3/31)!10%!
(5/27)!!18%!!!!!!!!!!(p=0.05)!
Diarrhoea!
(3/30)!10%!
(3/27)!13%!!!!!!!!!!!(p=0.81)!
Constipation!
(5/29)!17%!
(9/27)!33%!!!!!!!!!!!(p=0.04)!
Anorexia!
(4/31)!14%!
(9/27)!33%!!!!!!!!!!!(p=0.02)!
Fatigue!
(13/31)!41%!
(15/27)!55%!!!!!!!!!(p=0.02)!
Dyspnoea!
(8/31)!26%!
10/27)!38%!!!!!!!!!!(p=0.03)!
Pain!
(11/31)!36%!
(14/27)!51%!!!!!!!!!(p=0.02)!!!!!!!!
Weight!loss!
(4/29)!14%!
(2/24)!!8%!!!!!!!!!!!!(p=0.69)!!!!!!!!!!!!!!!!
Weight!gain!
(6/29)!21%!
(3/26)!!12%!!!!!!!!!!(p=0.37)!
Oedema!
(8/29)!28%!
(12/27)!44%!!!!!!!!!(p=0.05)!
!

Transdermal*oestrogen*in*prostate*cancer*
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100mcg/day$patch,$33$patients$(82.5%)$onto$200mcg/day$and$24$patients$(60%)$went$
onto$300mcg/day$patch$(Table$3).$
$
Table$3:$PSA,$estradiol,$SHBG,$testosterone,$LH/FSH$at$start$of$increasing$TDE$dose:$
$
$
50mcg/day$
100mcg/day$
200mcg/day$
300mcg/day$
End$of$
treatment$$
$
$
$
$
n$
40$
39$
33$
24$
40$
Median$PSA$
(mg/ml)$
151$$
(25-1386)$
149$$
(42-2135)$
160$$
(15-1777)$
163$$
(14-1506)$
441$$
(21.8-2650)$
Median$plasma$
estradiol$
(pg/ml)$
41$$
(0-137)$
117$$
(25-323)$
187$$
(66-1109)$
577$$
(135-1801)$
573$$
(37-3094)$
Median$plasma$
SHBG$(nmol/l)$
$$
$
40$(14-70)$
54$(18-148)$
63$(17-113)$
76$(42-120)$
76$(40-157)$
Plasma$
testosterone$
(nmol/l)$
$
0.7$(0.4-5.7)$
0.7$(0.4-4.6)$
0.6$(0.4-4.3)$
0.6$(0.2-2.5)$
0.7$(0.4-2.1)$
LH$(IU/l)$
$
0.3$$
(0.1-23.2)$
0.3$$
(0.1-17.3)$
0.3$$
(0.2-15.8)$
0.2$$
(0.1-4.8)$
0.2$$
(0.1-0.5)$
FSH$(IU/l)$
3.8$$
(1.4-83.7)$
3.0$$
(0.2-29.2)$
1.4$$
(0.2-33.1)$
0.5$$
(0.2-6.2)$
0.2$$
(0.1-2.5)$
$

Transdermal*oestrogen*in*prostate*cancer*
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PSA$Change$
5/40$patients$ (13%)$ had$>50%$ reduction$for$ at$ least$1$ month$at$ any$ TDE$ dose.$ The$
median$ progression-free$ survival$ was$ 4.6$ months$ (95%$ CI$ 1.7$ to$ 6.2$ months).$ 2/39$
patients$ (5%)$ had$ a$ confirmed$ PSA$ reduction$ >50%$ at$ 50mcg/day$ and$ a$ further$ 2$
patients$(5%)$at$100mcg/day.$There$were$no$reductions$in$PSA$at$200mcg/day.$1/24$
patients$(4.3%)$ had$ a$ reduction$ of$ >50%$ at$ 300mcg/day$(Figure$ 1).$Correlation$ was$
seen$between$a$rise$in$ SHBG$ and$PSA$decline$as$well$as$between$ plasma$ oestradiol$
and$PSA$response$except$at$50mcg/day.$
$
The$ median$ maximum$ change$ in$ PSA$ was$ -21%$ (range$ -94.8$ to$ +242.7%).$ The$
percentage$achieving$PSA$control$i.e.$stable$or$reduction$in$PSA$for$at$least$1$month$
was$53%$ (21/40$ patients)$at$ 50mcg/day,$ 53%$(21/39$patients)$ at$ 100mcg/day,$52%$
(17/33$ patients)$ at$ 200mcg/day$ and$ 50%$ (12/24$ patients)$ at$ 300mcg/day$ and$ 55%$
(22/40$ patients)$ as$ a$whole.$ 18$ patients$ (45%)$ developed$ symptomatic$progression$
and$dropped$out$prior$to$maximum$dose$escalation.$
$
$
$
$
$
$

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*
Figure$1$-$Waterfall$plots$for$the$changes$in$PSA$for$each$dose$of$transdermal$
oestradiol:$Graphs$demonstrate$respective$PSA$changes$at$(a)$50,$(b)$100,$(c)$200$and$
(d)$300$mcg$of$oestradiol.$
$
-100
-50
0
50
100
150
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37
(b)
-100
0
100
200
300
400
1357911 13 15 17 19 21 23 25 27 29 31 33
(c)
-100 .0
-50. 0
0.0
50 .0
10 0.0
15 0.0
20 0.0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
(d)
-100
-50
0
50
100
150
200
250
1357911 13 15 17 19 21 23 25 27 29 31 33 35 37 39
(a)

Transdermal*oestrogen*in*prostate*cancer*
18*
*
Survival$
Median$time$on$treatment$measured$5.5$months$(4.6-8.6$months$95%$C.I.).$Median$
survival$was$19.3$months$(interquartile$range$5.2-16.7$months).$Patients$with$normal$
alkaline$phosphatase$had$significantly$longer$time$on$treatment$and$overall$survival$
(OS)$ 9.1$ versus$ 4.2$ months$(p=0.0005)$ and$ 24.5$ versus$ 13.1$ months$ (p=0.001)$
respectively.$$
$
Time$on$treatment$and$OS$were$also$ significantly$longer$ in$patients$whose$ baseline$
Hb$was$greater$than$the$cohort$median:$8.15$months$vs$ 4.65$months$(p=0.005)$and$
24$vs$13.1$months$(p=0.066)$respectively.$$
$
Patients$with$baseline$PSA$less$than$the$median$also$had$a$longer$time$on$treatment$
and$ OS:$ 8.7months$ vs$ 4.35$ months$ (p=0.007)$ and$ 24.5$ vs$ 9.5$ months$ (p=0.0008)$
respectively.$
$
Diethylstilbestrol$
20$patients$received$diethylstilbestrol$post$TDE.$16$(80%)$had$a$decline$in$PSA$and$10$
(50%)$ had$ a$ >50%$ decline.$The$ median$ survival$ from$ the$ start$ of$ diethylstilbestrol$

Transdermal*oestrogen*in*prostate*cancer*
19*
*
was$46$months$in$those$who$had$a$50%$response$(range$6.2$–$NR)$vs$6.9$months$for$
those$who$did$not$(range$1.6-26.3)$($p=0.13)$
$
Quality$of$Life$
Mean$ standardized$ Quality$ of$ Life$ (QOL)$ scores$ initially$deteriorated$ on$ treatment$
compared$ to$ baseline$(QOL$ global$ score$ =$ 55.3$ at$ start$ of$ study,$ 44.7$ at$ 1$ month,$
p=0.04)$but$this$was$not$significant$at$4$months$of$treatment$(QOL$global$score$=$46,$
p=0.18).$In$addition,$hot$flushes$were$significantly$reduced$by$the$treatment.$
$$

Transdermal*oestrogen*in*prostate*cancer*
20*
*
Discussion$
Traditionally$ the$ hormonal$ targets$ for$ prostate$ cancer$ have$ focused$ on$ negating$
androgen$ action;$ however$ recent$ evidence$ from$ epidemiological$and$experimental$
data$have$elucidated$a$role$of$oestrogens$in$prostate$development$and$progression.$
The$prostate$expresses$both$oestrogen$receptor$alpha$(ERα)$and$oestrogen$receptor$
beta$(ERβ)$and$the$mechanism$of$action$of$oestrogen$in$prostate$cancer$is$likely$to$be$
multi-factorial$(20).$Most$evidence$suggests$that$ERα$mediates$the$harmful$effects$of$
oestrogen$ in$ the$ prostate$(21).$ Furthermore,$ ERα$ has$ been$ correlated$ with$ the$
tumour$ promoting$ function$ of$ TMPRSS2-ERG$ fusion,$ a$ major$ driver$ of$ prostate$
carcinogenesis$(22).$ In$ addition,$ the$ progressive$ emergence$ of$ ERα$ and$ ERα-
regulated$genes$during$prostate$cancer$progression$and$hormone$refractory$ disease$
suggests$that$these$tumours$can$bypass$the$AR$by$using$oestrogens$for$their$growth$
(21).$The$role$of$ERβ$in$the$prostate$remains$unclear$with$most$evidence$suggesting$
that$ ERβ$ is$ tumour$ suppressive$(23),$ however,$there$ is$ increasing$ evidence$ that$
isoforms$of$ERβ$may$be$oncogenic$(24,$25).$Finally,$it$has$been$shown$that$oestradiol$$
suppresses$tissue$ growth$ in$ vitro$ via$ ER-independent$ $mechanisms$ as$ well$ (26).$
Clinical$ trials$ using$oestrogen$ receptor-selective$ agents$ have$ not$ shown$ any$
improvements$in$clinical$outcomes$so$far$(20).$$
$

Transdermal*oestrogen*in*prostate*cancer*
21*
*
Our$cohort$of$patients’$response$to$TDE$was$modest$but$significant.$This$group$had$
been$pre-treated$with$GnRH$analogues$and$steroid$therapy$and$had$advanced$cancer$
as$demonstrated$by$resistance$to$castrate$levels$of$testosterone$and$a$median$PSA$of$
151.$A$significant$proportion$(26%)$were$Performance$Status$(PS)$2-3$and$were$thus$
inappropriate$for,$or$had$declined$Docetaxel$chemotherapy.$The$majority$of$patients$
had$ been$ on$ treatment$ for$ some$ time,$ with$ median$ time$ from$ diagnosis$ to$
development$of$castration$resistant$disease$of$38$months.$
$
A$ PSA$ response$ of$ >50%$ was$ seen$ in$ 13%$ of$ patients$ at$ any$ TDE$ dose.$ In$ 56%$ of$
patients,$TDE$use$at$any$dose$was$associated$with$either$ a$fall$ in$ PSA$ or$ stable$PSA.$
This$study$commenced$prior$to$the$adoption$of$PCWG-2$criteria$(6),$which$advises$12$
weeks$ of$ drug$ therapy$ prior$ to$ a$ confirmed$ rise$ in$ PSA$ rather$ than$ the$ 35-42$days$
followed$in$this$study.$This$may$have$resulted$in$underestimation$of$response$to$TDE.$$
$
Median$ time$ on$ treatment$ was$5.5$ months$ while$ the$ median$ time$ to$ progression$
using$ Kaplan-Meier$ estimates$ was$ 4.6$ months$ (1.7-6.2$ months).$ Median$ overall$
survival$ for$ this$ cohort$ was$ 19.3$ months$which$ compares$ favourably$ with$ overall$
survival$ in$ patients$ with$ metastatic$ CRPC$ receiving$ Docetaxel$ in$ the$ TAX-327$ trial$
(27).$Some$better$prognostic$groups$were$identified:$patients$with$a$ normal$alkaline$
phosphatase,$ or$ Hb$ >median$ were$ predictive$ factors$ for$ longer$ time$ on$ treatment$

Transdermal*oestrogen*in*prostate*cancer*
22*
*
and$greater$overall$survival.$In$those$ patients$ who$had$a$ 50%$PSA$response,$overall$
survival$was$excellent$at$46$months.$
$
Oestrogens$ are$ also$ known$ to$ have$ bone$protective$ effects$(28).$ Prostate$ cancer$
patients$with$a$high$ incidence$ of$bony$metastases$ and$ prolonged$LHRH$ agonist$ use$
are$ at$ high$ risk$ of$ pathological$ fractures$ (4).$ Reassuringly$ no$ skeletal$ events$ were$
recorded$in$this$study.$
$
Oral$DES$has$been$shown$to$have$activity$in$CRPC$(29).$$Shamash$ et$al,$conducted$a$
Phase$III$trial$using$immediate$or$deferred$DES$in$conjunction$with$dexamethasone$in$
CRPC$(30).$ Immediate$ DES$ was$ not$ superior$ to$ delayed$ DES$ with$ regards$ to$ PSA$
response$ rate$ or$ progression$ free$ survival$ (RR$ 68%$ immediate$ vs$ 64%$ deferred,$
p=0.49).$Given$the$high$incidence$of$VTE$with$immediate$DES$(22%$vs$11%),$DES$use$
was$not$recommended$until$failure$of$dexamethasone.$In$our$cohort,$there$was$one$
vascular$ event$ recorded;$a$ retinal$ artery$ occlusion$which$ was$ not$ a$ VTE.$ This$
supports$the$ belief$that$ TDE$has$a$ lower$ VTE$ side$ effect$ profile$than$ DES.$TDE$ may$
therefore$ be$ an$ option$ prior$ to$ DES$ therapy$ and$ a$ trial$ in$conjunction$with$
dexamethasone$may$be$appropriate.$$
$

Transdermal*oestrogen*in*prostate*cancer*
23*
*
Furthermore,$ there$ was$ significant$ response$ to$ DES$ after$ TDE$ treatment$ indicating$
there$possible$lack$of$cross$resistance$between$these$two$treatments.$The$activity$of$
DES$ after$ TDE$ suggests$ that$ the$ mechanism$ of$ action$ of$ transdermal$ and$ oral$
oestrogens$upon$CRPC$is$ not$ equivalent$and$ warrants$further$investigation.$There$is$
evidence$ of$ endocrine$ re-sensitisation$on$ discontinuing$ GnRH$ analogues$ whilst$ on$
alternative$therapy.In$another$study$by$Shamash$et$al,$for$example,$there$is$evidence$
of$ re-sensitisation$to$ hormonal$ therapy$ by$ discontinuing$ GnRH$ analogues$ during$
docetaxel$chemotherapy$(31).$Therefore,$ it$is$ possible$that$this$ re-sensitization$also$
applies$ to$ discontinuation$ of$ GnRH$ due$ to$ oestrogen$ use$ and$ would$ be$ very$
interesting$to$study$in$more$detail.$$
$
In$addition,$in$this$study$we$have$shown$that$TDE$affected$SHBG$in$a$dose-dependent$
fashion,$ and$ increased$ SHBG$ levels$ were$associated$ with$ a$ PSA$ response.$ This$
suggests$that$ SHBG$ may$ play$a$ role$ in$ driving$ the$ prostate$ cancer$ response$and$
correlates$with$the$fact$that$at$the$lowest$dose,$a$rise$in$SHBG$correlated$with$a$fall$
in$ PSA.$ Alterations$ in$ SHBG$ can$ alter$ the$ equilibrium$ between$ bound$ and$ free$
androgens$ affecting$ the$ availability$ of$ androgens$ to$ induce$ androgen$ receptor$
responses$ (32)$and$ this$ may$ be$ a$pathway$ for$ oestrogen$ to$ exert$ its$ influence$ on$
CRPC.$ The$ significance$ of$ SHBG$ remains$ under-investigated$ in$ CRPC$but$ the$
association$seen$in$this$trial$suggests$it$should$be$investigated$further.$

Transdermal*oestrogen*in*prostate*cancer*
24*
*
Increasing$ the$ TDE$ dose$ above$ 200mcg/day$ did$ not$ increase$ the$ PSA$ response$
observed.$The$number$of$patients$included$in$the$trial$was$small$and$a$dose$response$
may$ have$ been$ observed$ had$ more$ patients$ been$ included.$ In$ addition,$ it$ may$ be$
that$ for$ some$ patients$ where$ a$ PSA$ response$ at$ a$ lower$ dose$ was$ not$ seen,$
resistance$to$TDE$had$already$ developed$ and$this$could$not$be$ overcome$ with$dose$
increases.$
$
There$ are$ a$ number$ of$ limitations$ to$ our$ study.$ This$ was$ a$ small$ Phase$ II$ study$
involving$ 40$ patients$ in$ 2$ institutions$ and$ drawing$ conclusions$ as$ to$ the$ efficacy$ of$
TDE$in$the$wider$population$of$patients$with$CRPC$is$difficult.$In$addition,$there$was$
no$$use$of$routine$radiological$assessment$during$therapy.$In$fact,$in$many$studies$of$
second$generation$agents,$PSA$response$is$still$an$important$and$easy$way$to$assess$
early$response$however$it$is$clear$that$benefit$is$sometimes$seen$when$PSA$remains$
stable$or$ only$ slowly$increases.$ The$ dose$ titration$ in$the$ study$design$ meant$that$it$
was$much$harder$to$show$large$PSA$responses$as$TDE,$was$only$increased$if$PSA$rose.$
In$addition,$patients$came$off$the$study$ with$predefined$rises$in$PSA$which$may$not$
have$been$clinically$significant$again,$leading$to$possible$under$reporting$of$efficacy.$
Furthermore,$this$study$was$conducted$prior$to$the$routine$use$of$second$generation$
anti-androgens$and$ clearly$ it$ would$ be$ interesting$ to$ know$ whether$ there$ was$ any$
cross-resistance$ between$ them$ and$ transdermal$ oestradiol.$ None$ of$ the$ patients$

Transdermal*oestrogen*in*prostate*cancer*
25*
*
received$ prior$ chemotherapy$for$ castration-resistant$ disease$ which$would$ also$ be$
standard$nowadays$for$fit$patients.$
$
Finally,$clinical$trials$are$currently$investigating$the$use$of$TDE$in$metastatic$prostate$
cancer$in$the$hormone$sensitive$setting.$For$example,$the$PATCH$trial$(NCT00303784)$
compares$ the$ efficacy$ and$ safety$ of$ TDE$ vs$ GnRH$ analogues$ in$ men$ with$ locally$
advanced$ and$ metastatic$ prostate$ cancer$ and$ has$ so$ far$ recruited$ >2000$patients$
(33).$ The$ initial$ pilot$ phase$ showed$ that$ TDE$ achieved$ equivalent$ castrate$ levels$ of$
testosterone$ to$ GnRH$ analogues$ without$ the$ previously$ observed$ rates$ of$
cardiovascular$ toxicity$ seen$ with$ oral$ oestrogen$ (15).$ Furthermore,$ the$ STAMPEDE$
trial$(NCT00268476)$now$includes$a$ ‘TDE$ arm’$since$2017$and$this$will$compare$TDE$
to$ ADT$and$ together$ with$ the$ PATCH$ trial$ will$ be$ able$ to$ define$ the$ role$ of$ this$
treatment$in$metastatic$hormone$sensitive$prostate$cancer$(34).$
$
Conclusion$
This$ study$demonstrated$ that$ TDE$ is$ a$ low$ toxicity$ treatment$ that$ may$ provide$
control$ of$ CRPC$ after$ failure$ of$ steroid$ therapy$and$ that$ a$ dose$ of$ 200mcg/day$ -$
300mcg/day$has$an$acceptable$efficacy$/$toxicity$profile.$$The$low$toxicity$and$lack$of$
cross$ reaction$ with$ DES$ suggest$ it$ is$ a$ reasonable$ pre-DES$ therapy$ and$ could$ be$
considered$ as$ an$ alternative$ to$ novel$ anti-androgen$ therapies$ or$ as$ alternative$ to$

Transdermal*oestrogen*in*prostate*cancer*
26*
*
Docetaxel$chemotherapy$particularly$in$less$fit$patients.$The$most$significant$adverse$
effect$ is$ gynaecomastia.$ $ The$ correlation$ of$ SHBG$ levels$ with$ TDE$dose$ and$ PSA$
response$ suggest$ that$ modulation$ of$ SHBG$ level$ by$ oestrogens$ may$ play$ an$
important$role$in$the$effect$of$oestrogens$on$CRPC.$In$addition,$the$finding$ that$DES$
remains$active$after$TDE$suggests$differing$mechanisms$of$action$on$CRPC$dependent$
on$the$ route$ given.$$ It$would$ therefore$appear$that$ TDE$ is$ a$ safe$ and$valid$ therapy$
and$that$there$is$much$more$to$learn$about$the$role$of$oestrogens$in$CRPC.$$
$
$
Clinical$practice$points$
Oral$systemic$oestrogen$treatment,$in$the$form$of$diethylstilbestrol$(DES),$was$widely$
used$ in$ prostate$ cancer$ and$ castration-resistant$ disease.$Their$ use,$ however,$ was$
associated$with$increased$risk$of$cardiovascular$and$thromboembolic$events$resulting$
from$ the$ first-pass$ metabolism$ in$ the$ liver.$ TDE$ avoids$ this$ effect$ and$ offers$ an$
alternative$and$potentially$safer$means$of$androgen$suppression.$
TDE$ used$ in$ this$ population$ of$ patients$ with$ CRPC$ post$ GHRHa$ and$ DES$ treatment$
was$found$to$be$safe$and$well$tolerated.$Importantly$TDE$lead$to$PSA$decline$of$>50%$
in$13%$of$patients$with$a$median$progression-free$survival$of$4.6$months.$$
Optimal$ inhibition$ of$ the$ AR$ signaling$ pathway$ remains$ an$ important$ target$in$ the$
setting$of$CRPC$and$the$use$of$TDE$as$an$alternative$modality$of$maintaining$castrate$

Transdermal*oestrogen*in*prostate*cancer*
27*
*
levels$of$testosterone$is$a$possible$option$especially$for$the$older$and$less$fit$patients$
who$ might$ not$ tolerate$ chemotherapy$or$ second-generation$ anti-androgens$ and$
should$always$be$considered.$These$results$are$also$significant$in$the$rapidly$evolving$
treatment$setting$ of$metastatic$ castration-resistant$ prostate$cancer.$Given$that$ this$
study$was$conducted$during$a$period$where$second-generation$anti-androgens$were$
not$approved$or$available,$the$optimum$treatment$sequence$of$TDE$and$other$novel$
that$modulate$the$AR$pathway$is$currently$unclear$and$further$trials$will$need$to$be$
performed$to$determine$this.$ $

Transdermal*oestrogen*in*prostate*cancer*
28*
*
Declarations$of$interests$
None$Declared$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$

Transdermal*oestrogen*in*prostate*cancer*
29*
*
Funding$
The$Orchid$Cancer$Appeal$funded$the$clinical$trials$nurse.$
$
$ $

Transdermal*oestrogen*in*prostate*cancer*
30*
*
Acknowledgments:$$
We$would$like$to$thank$ Dr$S.$Gibbs,$ consultant$ clinical$oncologist,$ Barking$ Havering$
and$Edbridge$NHS$trust$for$referring$patients$for$this$study.$$
$
$$

Transdermal*oestrogen*in*prostate*cancer*
31*
*
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30.* Shamash* J,* Powles* T,* Sarker* SJ,* Protheroe* A,* Mithal* N,* Mills* R,* et* al.* A* multi-centre*
randomised* phase* III* trial* of* Dexamethasone* vs* Dexamethasone* and* diethylstilbestrol* in*
castration-resistant* prostate* cancer:* immediate* vs* deferred* Diethylstilbestrol.* Br* J* Cancer.*
2011;104(4):620-8.*
31.* Shamash* J,* Davies* A,* Ansell* W,* McFaul* S,* Wilson* P,* Oliver* T,* et* al.* A* phase* II* study*
investigating* the* re-induction* of* endocrine* sensitivity* following* chemotherapy* in* androgen-
independent*prostate*cancer.*Br*J*Cancer.*2008;98(1):22-4.*

Transdermal*oestrogen*in*prostate*cancer*
33*
*
32.* Rosner* W,* Hryb* DJ,* Khan* MS,* Nakhla* AM,* Romas* NA.* Sex* hormone-binding* globulin:*
anatomy*and*physiology*of*a* new* regulatory* system.* The*Journal*of*steroid*biochemistry*and*
molecular*biology.*1991;40(4-6):813-20.*
33.* Prostate*Adenocarcinoma*TransCutaneous*Hormones*(PATCH).*
34.* Systemic* Therapy* in* Advancing* or* Metastatic* Prostate* Cancer:* Evaluation* of* Drug*
Efficacy*(STAMPEDE).*
*

Clinical'practice'points'
Oral'systemic'oestrogen'treatment,'in'the'form' of'diethylstilbestrol' (DES),'was'
widely' used' in' prostate' cancer' and' castration-resistant' disease.'Their' use,'
however,' was' associated' with' increased' risk' of' cardiovascular' and'
thromboembolic'events'resulting'from'the'first-pass'metabolism'in'the'liver.'TDE'
avoids' this' effect' and' offers' an' alternative' and' potentially' safer' means' of'
androgen'suppression.'
TDE'used'in'this'population'of'patients'with'CRPC'post'GHRHa'and'DES'treatment'
was'found'to'be'safe'and'well'tolerated.'Importantly'TDE'lead'to'PSA'decline'of'
>50%'in'13%'of'patients'with'a'median'progression-free'survival'of'4.6'months.''
Optimal'inhibition'of'the'AR'signaling'pathway'remains'an'important'target'in'the'
setting' of' CRPC'and' the' use' of' TDE'as' an' alternative' modality' of' maintaining'
castrate'levels'of'testosterone' is' a' possible' option'especially' for'the'older' and'
less'fit'patients'who'might'not'tolerate'chemotherapy'or'second-generation'anti-
androgens'and'should'always'be'considered.'These'results'are'also'significant'in'
the'rapidly'evolving'treatment'setting'of'metastatic'castration-resistant'prostate'
cancer.'Given' that' this' study' was' conducted' during' a' period' where' second-
generation' anti-androgens' were' not' approved' or' available,' the' optimum'
treatment' sequence' of' TDE' and' other'novel' that'modulate' the' AR' pathway'is'
currently'unclear'and'further'trials'will'need'to'be'performed'to'determine'this.!
*Clinical Practice Points

Microabstract
*
We*aimed*to*investigate*the*role*and*safety*of*transdermal*oestrogen*therapy*in*
castrate*resistant*prostate*cancer.*Within*this*dose*escalation*study*we*observed*
reduction*in*PSA*levels*at*all*doses*used.*In*addition,*no*venous*thromboembolic*
events*were*detected*making*the*use*of*transdermal*oestradiol*a*safe*treatment*
option*for*a*subgroup*of*patients*with*castration-resistant*prostate*cancer.*
!
*Micro-Abstract