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 [6–9]) 186 Experimental Oncology 26, 185-191, 2004 (September)

Flutamide The recommended dosage in monothe- rapy 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 mono- therapy are limited) Nilutamide has a longer half-life than flutamide has) It is possible of single daily dose) Side ef- fects are decreased adaptation to darkness, nausea, gy- necomastia, 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 [17–19]) 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 mono- therapy 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 cypro- terone 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 pa- tients suffering from prostate cancer T3–T4; NX–N0; Fig 2 The endocrine effects of the pure antiandrogens (LH — luteinizing hormone, T — testosterone, E — oestradiol, DHT — M0–M1) 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 steroidal in structure and three arms [21]) Moffat in 1990 compared goseriline have any antigonadotropic effects) Pure antiandrogens monotherapy (3)6 mg per month) versus cyproterone block androgen receptors in the diencephalons, inter- acetate 300 mg per day in M+ or T3–T4 patients and fering with the testosterone secretion [11, 12]) The rise found a shorter median survival median time in pa- in plasma testosterone is temporary and self limiting at tients receiving cyproterone acetate [22]) Thorpe et al a level of about 1)5 times the normal plasma testoste- (1996) compared goseriline acetate plus goseriline in rone levels) Libido and potency are persistent under a series of 525 patients (96% were M+)) There was no pure antiandrogen monotherapy) This phenomenon statistically significant difference in terms of median time seems to be due to the maintenance of normal or ele- to progression between the goseriline plus cyproter- vated testosterone levels) Flutamide, nilutamide, and one acetate arm and either monotherapy arm) But there bicalutamide belong to that chemical family) was a statistically significant difference with goseriline Experimental Oncology 26, 185-191, 2004 (September) 187 acetate) That result could be explained by the experi- only 38)5% and median progression – free survival and mental evidence that cyproterone acetate might be con- median survival were 9 and 23 months respectively) verted in the human body into a weak androgen [23]) The tolerance of this agent was acceptable [33]) Clas- Flutamide Lund and Rasmussen published in 1988 sical nilutamide side effects are loss of adaptation to the results of a prospective randomized study com- alcohol intolerance, nausea, darkness e)g) [34]) paring flutamide 750 mg per day versus estrogens (DES Bicalutamide This drug has been investigated in mono- 3 mg per day) in 40 patients with advanced disease) therapy at dosage of 50, 150 or more mg per day [35–38]) The authors found no statistically significant difference Tyrell in 1994 used bicalutamide 50 mg once daily in between the two arms in terms of response) Treatment a monotherapy protocol on 267 patients with advanced with stilboestrol caused more frequent and more se- prostate cancer) He observed breast tenderness in 63)4%, vere side effects than flutamide [24]) Delaere and Van breast swelling in 52)5% and hot–flushes in 23)5%) Par- in 1991 treated 40 patients with advanced disease by tial regression was observed in 55)5% of the patients, sta- administration of flutamide (750 mg per day)) They no- ble disease in 15)6% and progression in 17)1% [39]) ticed that flutamide is effective but the follow-up is too Chatelain et al (1994) reported French multicentric trial short to assess weather time to progression and sur- comparing bicalutamide monotherapy with surgical cas- vival rate are comparable with those of conventional tration + nilutamide) In the bicalutamide group, only 6 pa- hormone therapy [25]) Chang et al published in 1996 a tients withdrew because of adverse events as compared study of 92 patients with D2 disease randomized in two with 13 in the combined treatment group [40]) Verhelst therapeutic arms: flutamide 750 mg per day or estro- et al (1994) studied the endocrine profiles in patients with gens (DES 3 mg per day)) Estrogens therapy caused prostate cancer treated by administration of bicalutamide more serious cardiovascular or thromboembolic com- as monotherapy (150 mg per day)) The authors found an plications than flutamide [26–28]) This drug was not as increase in LH and testosterone levels with an excellent active as estrogens [29]) Boccon-Gibod et al (1997) androgen blockade [41]) studied 104 patients M+ randomized to receive fluta- In 1996 several authors (Solowan et al, Kolvenbag mide 750 mg per day or surgical castration) The au- et al, Iversen et al, and Bales et al) reported in their series thors noticed that flutamide could be a reasonable al- that monotherapy with 50 mg per day appeared to be ternative to orchidectomy in highly selected patients inferior to surgical orchidectomy) The authors proposed [30]) Oosterling et al (1996) compared monotherapy further randomized studies with higher doses [11, 42–47]) with flutamide: with MAB (maximal androgen blockade = Iversen et al (1994 and 1998) and Anderson et al (1998) orchidectomy + flutamide or administration of LH-RH reported their results concerning monotherapy with bi- agonists + flutamide) in a series of 905 patients with calutamide 150 mg per day) On patients with M0 disease, locally advanced or metastatic disease) The conclu- the agent is equivalent to castration in terms of patient’s sions of this study were that flutamide represented a survival) In M1 disease, the bicalutamide monotherapy valid therapeutic option for sexually active prostatic showed a shortfall in terms of survival with a difference in cancer patients wishing to preserve their potency [31]) median survival of 42 days) In quality of life evolution, A clinical study (EORTC protocol 30892 compares monotherapy showed a benefit in 2 domains concerning flutamide versus cyproterone acetate as monotherapy M0 disease and in 1 — concerning M1 disease) No ad- in M1 disease), has shown no difference in either sex- vantages for castration in any of the quality of life do- ual activity or libido between patients treated with ei- mains was observed) M0 or M1 patients) [48, 49]) ther cyproterone acetate (300 mg/day) or flutamide Discussion The studies of Huggins and collegues (250 mg/day), with 40% of patients on both forms of [50–52] were reported six decades ago and contribut- therapy (Table), maintaining potency [5]) At this time, ed in our understanding of the prostate gland cancer no difference is seen in the results in terms of time to and its treatment by endocrine therapy, retained some progression) Side effects are significantly more frequent degree of androgen dependence) Furthermore, in pre- with flutamide) Sexual activity seems to decrease pubertally castrated male did not develop the prostatic equally in the two arms of the study [32]) cancer suggesting an implication of androgens in the Nitulamide Studies concerning nilutamide are not pathogenesis of the disease [53]) Although references numerous and the drug is not recommended by its in the literature about the use of orchidectomy for the manufacturer for use in monotherapy) Decensi et al treatment of the enlarged prostate provided the scien- (1991) treated 26 patients with metastatic carcinoma tific basis for the use of endocrine therapy based on of the prostate by administration of nilutamide as a sin- the removal of the source of circulating plasma test- gle agent) In this study, objective response rate was osterone, either by bilateral orchidectomy, subcapsu- lar orchidectomy or by the administration of estrogens, 7DEOHà (257&à à IOXWDPLGHà YHUVXVà F\SURWHURQHà DFHWDWHà LQà JRRGà as the primary treatment for the management of meta- SURJQRVLVÃ0 ÃSURVWDWLFÃFDQFHUÃ6H[XDOÃDFWLYLW\ÃDQGÃOLELGRà  static advanced prostate cancer [54, 55, 56]) )OXWDPLGHà &\SURWHURQHÃDFHWDWHà 3DUDPHWHUVà 1XPEHUà Èà 1XPEHUà Èà Synthesis of the estrogen, diethylstilboestrol (DES) 0RUQLQJÃHUHFWLRQVà à à à à (Dodds et al, 1938) was timely, thereby providing the 6H[XDOÃUHVSRQVHà à à à à first orally active agent for the treatment of the prostate (UHFWLRQÃZLWKÃUHVSRQVHà à à à à 2UJDVPà à à à à cancer [57]) DES, which exercises its therapeutic re- (MDFXODWLRQà à à à à sult by inhibiting the release of luteinising hormone from à 188 Experimental Oncology 26, 185-191, 2004 (September) the pituitary gland and consequently, the synthesis and One of the main advantages of pure antiandrogen secretion of testosterone by the testes became the most monotherapy is the maintenance of libido and poten- generally accepted estrogen for the management of cy) Is it justified to maintain libido and potency at the the advanced disease) price of other and more troublesome side effects or even The endocrine therapy is only palliative) The ad- more at the price of earlier progression of the disease? ministration of DES, although effective and inexpen- Firstly, the question whether antiandrogen monothe- sive, was not without controversy and several studies rapy is equally effective to other forms of classical andro- directed attention to the potentially dose-related side gen deprivation is not completely resolved) The best hor- effects, such as cardiovascular problems, decreased monal treatment for prostate cancer must be defined) Sur- libido, gynecomastia, gastric disturbances and nausea gical orchidectomy is still considered as the gold standard [58–61]) At a dose of 3 mg/day DES was associated of endocrine treatment of the disease, but data now avail- with thromboembolic and cardiovascular complications able seem to demonstrate a little advantage, if any, to maxi- in nearly 30% of patients; but the parenteral adminis- mal androgen blockade, especially in patients with mini- tration of estrogen may offer a lower risk than an oral mal disease) The results of antiandrogen monotherapy are dosage [62]) On the other hand and on the basis of such patients would eventually be compared with MAB either removing the source of circulating testosterone, results) Cyproterone acetate has been compared with or restraining the intraprostatic biological action of estrogens and seems to be equally effective in major end 5a-dihydrotestosterone (DHT), new therapeutic im- points but, when compared with gosereline or gosereline provements were developed, although few drugs other plus cyproterone acetate, cyproterone acetate alone seems than DES, gained worldwide approval (Fig) 3)) to be slightly less effective) Flutamide monotherapy com- pared in limited studies with MAB, administration of estro- gens plus surgical orchidectomy, seems equally effective) Further studies are required to assess the dosage and the efficacy of bicatulamide in monotherapy) On a basic point of view, we must keep in mind that the use of steroidal antiandrogens in monotherapy decreases the plasma tes- tosterone and in the other hand, the use of pure antiandro- gens leads to a rise of testosterone) Steroidal antiandrogens have to compete, when binding to the androgen receptor, with smaller amounts of androgens) It is unlikely that pure antiandrogens can cause a maximal androgen blockade in comparison with a steroidal antiandrogen which basi- Fig 3 Endocrine therapy for advanced disease cally can [1–3]) The clinical data about antiandrogens in The natural course of the prostate cancer follows a monotherapy seem to demonstrate that these remarks are consistent biological process characterized by an unusu- not clinically significant) ally slow, although generally constant rate of growth Secondly, the antiandrogen side effects are not [63, 64]) This rate of development can be improved by negligible) In a review of different studies about fluta- genetic instability of the cancer, and however, that the mide, bicalutamide and nilutamide, Dole and Hold- clinical stage and tumor grade, influence the outcome and sworth (1997), concluded that nilutamide was some- the management [65]) The ultimate survival time depends what inferior to both flutamide and bicalutamide with on the prognostic factors present at initial diagnosis and regard of side effects) Flutamide side effects are well 50% of patient’s die of their disease, the remaining 50% defined: diarrhea (20%), gynecomastia (45%), hot die with the disease in various stages of progression) The flushes (2)5%), liver damages with increased levels of studies of Huggins claimed no more than a decline in the plasma aminotransferases (2)5%), nausea and vomi- level of serum phosphatases and an associated relief of ting (5%), and vertigo (2)5%)) Bicalutamide is associ- pain in patients with symptomatic disseminated disease, ated with less gastrointestinal effects than the fluta- treated by androgen [51]) mide and is not associated with pneumonitis, alcohol It is well known in ours days that the regulation of intolerance, or ocular defects which have been seen prostatic development is a most complicated biological with the administration of nilutamide) Nevertheless, process with cellular homeostasis sustained through major hepatic disturbances have been reported with of the equilibrium between growth stimulating and re- bicalutamide) The use of cyproterone acetate leads in straining factors which control cellular proliferation and most of the cases but not in all, to loss of libido and apoptosis) This process is under the modulating influ- potency) Gynecomastia in association with adminis- ence of intraprostatic DHT [66–68]) The DHT is impor- tration of cyproterone acetate is not significant) The most tant with regard to the androgenic action it exercises extensive study of cardiovascular side effects has been on the genome through its association with the andro- carried out by the EORTC-GU group and reported by gen receptor, like a DHT-AR complex [69, 70]) More- De Voogt in 1992) According to the data of this study, over, androgen withdrawal therapy can lead to a de- cyproterone acetate seems to be 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Ðàê ïðåäñòàòåëüíîé æåëåçû, çàíèìàþùèé âòîðîå ìåñòî â ñòðóêòóðå çëîêà÷åñòâåííûõ îïóõîëåé ó ìóæ÷èí, íàõîäèòñÿ â öåíòðå âíèìàíèÿ èññëåäîâàòåëåé Èçâåñòíî, ÷òî ðåãóëÿöèÿ ðîñòà îïóõîëè ïðåäñòàòåëüíîé æåëåçû ÿâëÿåòñÿ ñëîæíûì áèîëîãè÷åñêèì ïðîöåññîì Áîëåå òîãî, îáùåïðèçíàííî, ÷òî ðàçâèòîé ðàê ýòîãî îðãàíà ÿâëÿåòñÿ çàâèñèìûì îò àíäðîãåíîâ Çà ïîñëåäíèå 50 ëåò ïóòåì ñíèæåíèÿ óðîâíÿ àíäðîãåíîâ äîñòèãíóòû çíà÷èòåëüíûå óñïåõè â ëå÷åíèè ýòîãî çàáîëåâàíèÿ  íàñòîÿùåå âðåìÿ ðàê ïðåäñòàòåëüíîé æåëåçû äèàãíîñòèðóþò íà áîëåå ðàííèõ ñòàäèÿõ, à òåðàïèÿ óëó÷øàåò ðåçóëüòàòû âûæèâàåìîñòè è ïðîãíîç Ê ñîæàëåíèþ, ïðè ëå÷åíèè áîëüíûõ ñ ýòîé ïàòîëîãèåé âîçìîæíû ïîáî÷íûå ýôôåêòû, îòðèöàòåëüíî âëèÿþùèå íà êà÷åñòâî èõ æèçíè Õèðóðãè÷åñêàÿ èëè ôàðìàêîëîãè÷åñêàÿ êàñòðàöèÿ çíà÷èòåëüíî óõóäøàåò êà÷åñòâî æèçíè ïàöèåíòîâ (óòðàòà ïîëîâîãî âëå÷åíèÿ, îñòåîïîðîç, óìåíüøåíèå ìûøå÷íîé ìàññû è òä) Ìîíîòåðàïèÿ àíòèàíäðîãåíàìè ïðåäëàãàåòñÿ èíôîðìèðîâàííûì ïàöèåíòàì, æåëàþùèì ñîõðàíèòü ñåêñóàëüíóþ àêòèâíîñòü Âîçìîæåí ïåðîðàëüíûé ïðèåì ïðåïàðàòîâ, ÷òî óäîáíî è õîðîøî ïåðåíîñèòñÿ áîëüíûìè Äàííûé îáçîð ïîñâÿùåí ìîíîòåðàïèè àíòèàíäðîãåíàìè êàê ñïîñîáó âûáîðà ïðè ëå÷åíèè ïðîãðåññèðóþùåãî ðàêà ïðåäñòàòåëüíîé æåëåçû Êëþ÷åâûå ñëîâà: ïðîãðåññèðóþùèé ðàê ïðåäñòàòåëüíîé æåëåçû, ìîíîòåðàïèÿ, àíòèàíäðîãåíû

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