Monotherapy in Advanced Prostate Cancer: an Overview

Experimental Oncology 26, 185-191, 2004 (September) 185 Exp Oncol 2004 26, 3, 185-191 MONOTHERAPY IN ADVANCED PROSTATE CANCER: AN OVERVIEW Dimitrios Baltogiannis1,*, Xenophon Giannakopoulos1, Kostas Charalabopoulos2, Nikolaos Sofikitis1 1Department of Urology, Medical Faculty, University of Ioannina, Ioannina, Greece 2Department of Physiology, Clinical Unit, Medical Faculty, University of Ioannina, Ioannina, Greece Prostate cancer is the second leading malignancy in men associated with an enormous research interest in all aspects of the disease It is well recognized that the regulation of prostatic growth is a complicated biological process Further more the androgenic dependence of the advanced prostate cancer is well know and in the last 50 years significant progresses regarding the principle of deprivation of androgens for the treatment of the disease occured Prostate cancer is now diagnosed in earlier stages and treatment results in increased potential for cure or extension of overall survival Unfortunately, every treatment for prostate cancer has adverse effects with negative impact in health-related quality of life Surgical or pharmacological castration has a significant negative impact on quality of life in patients with prostate cancer (loss of sexuality, osteoporosis, and loss of muscle mass, eg) Antiandrogen monotherapy is considered to be a treatment in well-informed patients who wish to remain sexually active, can be administered orally, and is well tolerated by patients with prostate cancer This review is focused on antiandrogen monotherapy in the treatment of advanced prostate cancer Key Words: advanced prostate cancer, monotherapy, antiandrogens Improvements in prostate cancer detection lead to Surgical castration, estrogens and LH-RH agonists more frequent diagnosis of localized disease) Unfortu- decrease the plasma testosterone between 5 to 10% of nately, a lot of patients are discovered with advanced the original values) The withdrawal of testosterone and its disease) Despite the improvements in diagnostic me- local metabolite 5a-dihydrotestosterone (DHT), leads to thods and techniques as well as in surgical procedures, an average tumor volume decrease of about 35% but also after pathological analysis, a percentage of patients treat- to immediate side effects as loss of libido and potency, and ed with a radical intent by radical prostatectomy or maxi- to long term side effects as hot-flushes, osteoporosis, loss mum radiation therapy, presents a locally advanced of muscle mass, fatigue, weight gain and anemia [1]) disease) Among these patients, local control of the dis- Antiandrogens act by competitive blockade of tes- ease is not always possible and some of them will present tosterone and DHT binding to the nuclear androgen a recurrence of the disease) In such situations, total receptors in prostate cancer cells) There are two classes androgen deprivation remains the treatment of choice of androgen receptor antagonists: nonsteroidal or pure [1, 2]) Castration modalities are numerous (see below)) antiandrogens as well as steroidal antiandrogens [3]) This review article is devoted to monotherapy in ad- I) Steroidal antiandrogens A variety of progestational vanced prostate cancer, a title somewhat confused) Actu- steroids such as medroxyprogesterone acetate, hydroxy- ally, search in Medline under the word monotherapy shows progesterone acetate, cyproterone acetate and chlorma- that this word is used in very different situations (mono- dinone acetate was used as principal therapy [4]) Proges- therapy with radical surgery, radiation therapy with or with- tational steroids inhibit the secretion of LH from the pitu- out luteotropic releasing hormone (LHRH) agonists e)g))) itary gland as well as acting like an antiandrogen within Combined total androgen blockage compared to adminis- the prostate by competing with DHT for the androgen re- tration of hormonal monotherapy is a controversial subject) ceptor (AR), in this way influence the androgenic interac- This review will be focused on antiandrogen monotherapy tion of the DHT-AR complex with the genome (Fig) 1)) in the treatment of advanced prostate cancer) Several clinical promises have been reported in the lite- Antiandrogens Endocrine therapy of prostate cancer rature in use of these compounds) However, diminished is palliative and is applied to either locally advanced or libido and impotence were reported in over 80% of pa- metastatic prostate cancer) Androgen withdrawal can be tients in an early study with cyproterone acetate [5]) achieved by: surgical castration (alone or with antiandro- Cyproterone acetate (CPA), because of its proges- gens), medical castration: estrogens (diethylstilboestrol terone-like molecular structure, decreases the produc- (DES), 1 mg three times per day), LH-RH agonists (alone tion of luteinising hormone (LH) by the pituitary gland or with antiandrogens) and androgen total blockade at tar- and therefore has an additional effect in decreasing the get cells: steroidal or non steroidal (pure) antiandrogens) production of testosterone by the hormonal activity of the testis) That central action may explain the positive Received: March 1, 2004 effect of CPA in the treatment of hot flushes induced by Correspondence: Fax: +302651097069 E-mail: dbaltog@ccuoigr androgens withdrawal) The recommended dosage of Abbreviations used: AR androgen receptor; CPA cyproterone CPA in monotherapy is 100 mg two or three times per acetate; DES diethylstilboestrol; DHT 5a-dihydrotestoste- day) At that dosage, side effects include loss of libido rone; LH luteinising hormone; LHRH luteotropic releasing and potency, cardiovascular toxicity (mild), gynecomas- hormone; PSA prostate specific antigen tia and possible but unproved hepatic toxicity [69]) 186 Experimental Oncology 26, 185-191, 2004 (September) Flutamide The recommended dosage in monotherapy is 250 mg three times per day) Gastrointestinal and hepatic disturbances as well as gynecomastia have been reported) Diarrhoea, anorexia and nausea are other side effects [13, 14]) Nilutamide Investigations with nilutamide in monotherapy are limited) Nilutamide has a longer half-life than flutamide has) It is possible of single daily dose) Side effects are decreased adaptation to darkness, nausea, gynecomastia, alcohol intolerance, and possible pulmonary fibrosis) Fulminate hepatitis has also been reported [15]) Bicalutamide This drug has also a long half-life and can be given as a single daily dose) Dosage of 150 mg per Fig 1 Effect of progesterons on the synthesis of testosterone day seems to be required for monotherapy) In contrast to and on the intraprostatic effects of DHT on the genome (LH luteinizing hormone, T testosterone, E oestradiol, DHT flutamide and nilutamide, bicalutamide therapy appears not 5a-dihydrotestosterone, DNA deoxyribonucleic acid, AR to be associated with notable side effects [16]) Nether less, androgen receptor) fulminate hepatic failures has been reported [1719]) II) Pure antiandrogens) These compounds compete Rationale for antiandrogens monotherapy To- with the intraprostatic DHT, and because they are not day, available data seem not to reveal a clinically rele- progestional do not inhibit the pituitary gland (Fig) 2)) The vant advantage of any effective endocrine regimen and organic effect of the pure antiandrogen on the pituitary is of endocrine treatment in general in overall survival) as an antiandrogen, reacting with the negative feed-back Endocrine treatment is thus pure palliative treatment) control of testosterone on the gland) This interaction with For that reason, quality of live under endocrine treat- the hypothalamic-pituitary testicular axis results in an in- ment must be seriously considered) Some side effects crease in LH output and as a result an increased synthe- of classical surgical castration could be partially avoid- sis and secretion of testosterone from the testis gland) ed by non classical castration: delayed or intermittent Wherefore the aromatisation of the testosterone by tis- treatment, antiandrogen monotherapy) Antiandrogen sues will increase oestradiol levels in plasma and this can monotherapy could be an alternative therapeutic op- improve gynecomastia and nipple pain [10]) tion in some selected patients to prevent hot-flushes, loss of libido, lethargy, or impotence) Data about monotherapy with antiandrogens as cyproterone acetate, flutamide, nilutamide and bicalutamide are available in the literature as reported below) Results of antiandrogen monotherapy Cyproterone acetate Jacobi et al (1980) demon- strated that cyproterone acetate in monotherapy (300 mg weekly administered by intramuscular injec- tion) is comparable to estradiol undecylate (100 mg monthly) in terms of progression and survival rates [20]) Pavone-Macaluso et al (1986) and the EORTC GU group reported also in 1986 a study comparing cyproterone acetate 300 mg per day versus estrogens (DES 3 mg per day), versus medroxyprogesterone acetate (500 mg 3 times per week), followed by a maintenance dose of 200 mg per day orally in a series of 210 patients suffering from prostate cancer T3T4; NXN0; Fig 2 The endocrine effects of the pure antiandrogens (LH luteinizing hormone, T testosterone, E oestradiol, DHT M0M1) They noticed no difference in complete or par- 5a-dihydrotestosterone, DNA deoxyribonucleic acid, AR tial remission, in local tumor mass reduction, in the in- androgen receptor) cidence of side effects and complications between the These compounds are non

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