Phase II study of transdermal estradiol in androgen-independent prostate carcinoma
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CORRESPONDENCE Phase II Study of Transdermal Estradiol in Androgen-Independent Prostate Carcinoma W e read with interest results reported by Bland et al. 1 using trans- dermal estradiol in good performance status androgen indepen- dent prostate cancer patients experiencing early relapse and com- mend the authors’ efforts to investigate a strategy for delivering estrogen safely. A median time to progression of 12 weeks was dem- onstrated with no clinical evidence of thromboembolic events. The authors concluded a low overall activity for the regimen as a second- ary hormonal maneuver. Given the current results, we wonder if parenteral estrogen therapy used with systemic chemotherapy in androgen independent prostate cancer would provide for superior survival endpoints instead of a secondary hormonal maneuver alone. Indeed, the current standard in androgen independent stage is largely based on a chemohormonal intervention. The combination of paren- teral estrogen with chemotherapy in androgen independent stage is attractive, as the therapeutic advantages of estrogens, such as estro- gen mediated apoptosis 2 and bone strength preservation, may com- plement palliative chemotherapy in androgen independent stage. In this regard, we explored the effect of combination parenteral estrogen (intramuscular estradiol valerate) and chemotherapy on co- agulation and plasminogen system activation in androgen indepen- dent stage in a Phase I trial. 3 Our primary goal was to monitor coagulation and plasminogen system activation and was performed by using subclinical markers such as thrombin–antithrombin com- plex (TAT; reference range,1.0 – 4.1 /L) and quantitative D-dimer levels (QDD, range:0 –250 ng/mL) as surrogate markers predictive for thrombohemorrhagic complications. Three escalating doses (10mg, 20 mg, 40 mg) of intramuscular estradiol valerate were administered every 2 weeks in 12 patients. Before each estradiol valerate dose, these markers were measured, and patients with rising levels above base- line measurements were given once daily prophylaxis with 60 mg of low molecular weight heparin. We found that the majority of patients (10 of 12) had subclinical hemostatic activation as measured by rising plasma TAT and QDD levels after estradiol dosing, which returned to patient-specific baseline with daily prophylactic anticoagulation. No clinical thrombosis or hemorrhagic event was observed. Parenteral estrogen administration as shown by Bland et al. 1 in the current study and from our results during androgen independent stage is feasible as it does not appear to result in clinically evident thrombosis, but it can result in increased hemostatic activation, es- pecially if combined with chemotherapy. To explore the therapeutic advantages of estrogen therapy not limited to hormonal maneuvers, larger studies will likely need to define a role for prophylactic antico- agulation if estrogens are to be combined with chemotherapy. REFERENCES 1. Bland LB, Garzotto M, DeLoughery TG, Ryan CW, Schuff KG, Wersinger EM, et al.. Phase II study of transdermal estradiol in androgen-independent prostate carcinoma. Cancer. 2005;103:717–723. 234 © 2005 American Cancer Society DOI 10.1002/cncr.
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Transcript of Phase II study of transdermal estradiol in androgen-independent prostate carcinoma
CORRESPONDENCE
Phase II Study of Transdermal Estradiol inAndrogen-Independent Prostate Carcinoma
We read with interest results reported by Bland et al.1 using trans-dermal estradiol in good performance status androgen indepen-
dent prostate cancer patients experiencing early relapse and com-mend the authors’ efforts to investigate a strategy for deliveringestrogen safely. A median time to progression of 12 weeks was dem-onstrated with no clinical evidence of thromboembolic events. Theauthors concluded a low overall activity for the regimen as a second-ary hormonal maneuver. Given the current results, we wonder ifparenteral estrogen therapy used with systemic chemotherapy inandrogen independent prostate cancer would provide for superiorsurvival endpoints instead of a secondary hormonal maneuver alone.Indeed, the current standard in androgen independent stage is largelybased on a chemohormonal intervention. The combination of paren-teral estrogen with chemotherapy in androgen independent stage isattractive, as the therapeutic advantages of estrogens, such as estro-gen mediated apoptosis2 and bone strength preservation, may com-plement palliative chemotherapy in androgen independent stage.
In this regard, we explored the effect of combination parenteralestrogen (intramuscular estradiol valerate) and chemotherapy on co-agulation and plasminogen system activation in androgen indepen-dent stage in a Phase I trial.3 Our primary goal was to monitorcoagulation and plasminogen system activation and was performedby using subclinical markers such as thrombin–antithrombin com-plex (TAT; reference range,1.0 – 4.1 �/L) and quantitative D-dimerlevels (QDD, range:0 –250 ng/mL) as surrogate markers predictive forthrombohemorrhagic complications. Three escalating doses (10mg,20 mg, 40 mg) of intramuscular estradiol valerate were administeredevery 2 weeks in 12 patients. Before each estradiol valerate dose, thesemarkers were measured, and patients with rising levels above base-line measurements were given once daily prophylaxis with 60 mg oflow molecular weight heparin. We found that the majority of patients(10 of 12) had subclinical hemostatic activation as measured by risingplasma TAT and QDD levels after estradiol dosing, which returned topatient-specific baseline with daily prophylactic anticoagulation. Noclinical thrombosis or hemorrhagic event was observed.
Parenteral estrogen administration as shown by Bland et al.1 inthe current study and from our results during androgen independentstage is feasible as it does not appear to result in clinically evidentthrombosis, but it can result in increased hemostatic activation, es-pecially if combined with chemotherapy. To explore the therapeuticadvantages of estrogen therapy not limited to hormonal maneuvers,larger studies will likely need to define a role for prophylactic antico-agulation if estrogens are to be combined with chemotherapy.
REFERENCES1. Bland LB, Garzotto M, DeLoughery TG, Ryan CW, Schuff KG, Wersinger EM, et
al.. Phase II study of transdermal estradiol in androgen-independent prostatecarcinoma. Cancer. 2005;103:717–723.
234
© 2005 American Cancer SocietyDOI 10.1002/cncr.
2. Kohli M, Alikhan MA, Spencer HJ, Carter G. Phase I trial ofintramuscular estradiol valerate (I/M-E) in hormone refrac-tory prostate cancer. J Clin Oncology. 2004;22(14S):4726.
3. Robertson CM, Roberson KM, Padilla GM, O’Brien ET, CookJM, Kim CS, Fine RL. Induction of apoptosis by diethylstil-bestrol in hormone sensitive prostate cancer cells. J NatlCancer Inst. 1996; 88:908 –917.
Manish Kohli, M.D.
Division of Hematology/Oncology,University of Arkansas for Medical Sciences
and Central Arkansas Veterans Healthcare System,Little Rock, Arkansas
DOI 10.1002/cncr.21528Published online 13 November 2005 in Wiley InterScience
(www.interscience.wiley.com).
Author Reply
We applaud the authors for pursuing the interest-ing hypothesis that estrogens may enhance the
activity of chemotherapy in prostate cancer.Unlike these authors, we did not find evidence of
activation of coagulation with transdermal estradioltherapy.1 It is possible that this difference was due todifferences in pharmacokinetics of the intramuscularand transdermal formulation. Other explanationsshould also be considered. As the authors do not re-port the results of their assays in control groups ofpatients treated with intramuscular estradiol valeratealone or chemotherapy alone, it is difficult to ascertainwhether the observed changes in measures of coagu-lation were indeed related to estradiol or to the com-bination with chemotherapy. Clearly, further study isnecessary to more robustly characterize the effects ofparenteral estrogens on coagulation.
We would caution against making the assumptionthat biochemical evidence of coagulation activationcan be used as a surrogate for thromboembolic com-plications. Evidence for this assumption is lacking. Forexample, in a prospective observational study thatinvolved 21,690 participants, elevated D-Dimers wereassociated with an increased risk of subsequent ve-nous thrombosis in the general population, but inpatients with cancer, D-Dimer levels did not predictfuture venous thrombosis.2 Furthermore, we cautionagainst the use of anticoagulation therapy based onbiochemical evidence of coagulation activation alone.Before such clinical approaches can be recom-mended, a surrogacy relation between specificchanges in biochemical markers of coagulation andspecific adverse clinical outcomes needs to be estab-lished in prospective clinical trials. Then, the safetyand efficacy of anticoagulation therapy administeredon the basis of biochemical evidence of coagulationactivation must be prospectively tested.
We share the authors’ enthusiasm for furtherstudies of estrogen-based prostate cancer therapy.Based on preclinical evidence that diethylstilbestrolspecifically inhibits the expression of beta-tubulinType IVa, an isotype that is thought to mediate taxaneresistance3–5 and improves efficacy of docetaxel in axenograft model6 we joined Dr. Bruce Montgomery ofthe University of Washington to investigate the safetyand efficacy of diethylstilbestrol with docetaxel in an-drogen-independent prostate cancer.
We also believe that the greatest promise of paren-teral estrogens may lie in front-line hormonal therapyfor prostate cancer. To this end, we are developing adouble-blind randomized trial that will compare trans-dermal estradiol to conventional androgen deprivationin the initial hormonal management of prostate cancer.
REFERENCES1. Bland LB, Garzotto M, DeLoughery TG, Ryan CW, Schuff KG,
Wersinger EM, et al. Phase II study of transdermal estradiolin androgen-independent prostate carcinoma. Cancer. 2005;103:717–723.
2. Cushman M, Folsom AR, Wang L, et al. Fibrin fragmentD-dimer and the risk of future venous thrombosis. Blood.2003;101:1243–1248.
3. Kavallaris M, Kuo DY, Burkhart CA, et al. Taxol-resistantepithelial ovarian tumors are associated with altered expres-sion of specific beta-tubulin isotypes. J Clin Invest. 1997;100:1282–1293.
4. Montgomery RB, Guzman J, O’Rourke DM, Stahl WL. Expres-sion of oncogenic epidermal growth factor receptor familykinases induces paclitaxel resistance and alters beta-tubulinisotype expression. J Biol Chem. 2000;275:17358–17363.
5. Ranganathan S, Benetatos CA, Colarusso PJ, Dexter DW,Hudes GR. Altered beta-tubulin isotype expression in pacli-taxel-resistant human prostate carcinoma cells. Br J Cancer.1998;77:562–566.
6. Montgomery RB, Bonham M, Nelson PS, et al. Estrogen effectson tubulin expression and taxane mediated cytotoxicity inprostate cancer cells. Prostate. 2005; epub ahead of print.
Lisa B. Bland, M.D., M.P.H.
Department of Urology and Renal TransplantationOregon Health & Science University
Portland, Oregon
Tomasz M. Beer, M.D.
Department of Hematology & Medical Oncologyand Oregon Health & Science
University Cancer InstituteOregon Health and Science University
Portland, Oregon
Mark Garzatto, M.D.
Urology Section, Portland VA Medical Centerand Division of Urology and Renal Transplantation
Oregon Health & Science UniversityPortland, OregonDOI 10.1002/cncr.21529
Published online 13 November 2005 in Wiley InterScience(www.interscience.wiley.com).
Correspondence 235
