Experimental Oncology 26, 185-191, 2004 (September) Exp Oncol 2004 26, 3, 185-191
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MONOTHERAPY IN ADVANCED PROSTATE CANCER: AN OVERVIEW Dimitrios Baltogiannis1,*, Xenophon Giannakopoulos1, Kostas Charalabopoulos2, Nikolaos Sofikitis1 1 Department of Urology, Medical Faculty, University of Ioannina, Ioannina, Greece 2 Department 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, e.g.). 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 more frequent diagnosis of localized disease. Unfortunately, a lot of patients are discovered with advanced disease. Despite the improvements in diagnostic methods and techniques as well as in surgical procedures, after pathological analysis, a percentage of patients treated with a radical intent by radical prostatectomy or maximum radiation therapy, presents a locally advanced disease. Among these patients, local control of the disease is not always possible and some of them will present a recurrence of the disease. In such situations, total androgen deprivation remains the treatment of choice [1, 2]. Castration modalities are numerous (see below). This review article is devoted to monotherapy in advanced prostate cancer, a title somewhat confused. Actually, search in Medline under the word monotherapy shows that this word is used in very different situations (monotherapy with radical surgery, radiation therapy with or without luteotropic releasing hormone (LHRH) agonists e.g.). Combined total androgen blockage compared to administration of hormonal monotherapy is a controversial subject. This review will be focused on antiandrogen monotherapy in the treatment of advanced prostate cancer. Antiandrogens. Endocrine therapy of prostate cancer is palliative and is applied to either locally advanced or metastatic prostate cancer. Androgen withdrawal can be achieved by: surgical castration (alone or with antiandrogens), medical castration: estrogens (diethylstilboestrol (DES), 1 mg three times per day), LH-RH agonists (alone or with antiandrogens) and androgen total blockade at target cells: steroidal or non steroidal (pure) antiandrogens. Received: March 1, 2004. Correspondence: Fax: +302651097069 E-mail:
[email protected] Abbreviations used: AR androgen receptor; CPA cyproterone acetate; DES diethylstilboestrol; DHT 5a-dihydrotestosterone; LH luteinising hormone; LHRH luteotropic releasing hormone; PSA prostate specific antigen.
Surgical castration, estrogens and LH-RH agonists decrease the plasma testosterone between 5 to 10% of the original values. The withdrawal of testosterone and its local metabolite 5a-dihydrotestosterone (DHT), leads to an average tumor volume decrease of about 35% but also to immediate side effects as loss of libido and potency, and to long term side effects as hot-flushes, osteoporosis, loss of muscle mass, fatigue, weight gain and anemia [1]. Antiandrogens act by competitive blockade of testosterone and DHT binding to the nuclear androgen receptors in prostate cancer cells. There are two classes of androgen receptor antagonists: nonsteroidal or pure antiandrogens as well as steroidal antiandrogens [3]. I. Steroidal antiandrogens. A variety of progestational steroids such as medroxyprogesterone acetate, hydroxyprogesterone acetate, cyproterone acetate and chlormadinone acetate was used as principal therapy [4]. Progestational steroids inhibit the secretion of LH from the pituitary gland as well as acting like an antiandrogen within the prostate by competing with DHT for the androgen receptor (AR), in this way influence the androgenic interaction of the DHT-AR complex with the genome (Fig. 1). Several clinical promises have been reported in the literature in use of these compounds. However, diminished libido and impotence were reported in over 80% of patients in an early study with cyproterone acetate [5]. Cyproterone acetate (CPA), because of its progesterone-like molecular structure, decreases the production of luteinising hormone (LH) by the pituitary gland and therefore has an additional effect in decreasing the production of testosterone by the hormonal activity of the testis. That central action may explain the positive effect of CPA in the treatment of hot flushes induced by androgens withdrawal. The recommended dosage of CPA in monotherapy is 100 mg two or three times per day. At that dosage, side effects include loss of libido and potency, cardiovascular toxicity (mild), gynecomastia and possible but unproved hepatic toxicity [69].
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Fig. 1. Effect of progesterons on the synthesis of testosterone and on the intraprostatic effects of DHT on the genome (LH luteinizing hormone, T testosterone, E oestradiol, DHT 5a-dihydrotestosterone, DNA deoxyribonucleic acid, AR androgen receptor)
II. Pure antiandrogens. These compounds compete with the intraprostatic DHT, and because they are not progestional do not inhibit the pituitary gland (Fig. 2). The organic effect of the pure antiandrogen on the pituitary is as an antiandrogen, reacting with the negative feed-back control of testosterone on the gland. This interaction with the hypothalamic-pituitary testicular axis results in an increase in LH output and as a result an increased synthesis and secretion of testosterone from the testis gland. Wherefore the aromatisation of the testosterone by tissues will increase oestradiol levels in plasma and this can improve gynecomastia and nipple pain [10].
Fig. 2. The endocrine effects of the pure antiandrogens (LH luteinizing hormone, T testosterone, E oestradiol, DHT 5a-dihydrotestosterone, DNA deoxyribonucleic acid, AR androgen receptor)
These compounds are non steroidal in structure and have any antigonadotropic effects. Pure antiandrogens block androgen receptors in the diencephalons, interfering with the testosterone secretion [11, 12]. The rise in plasma testosterone is temporary and self limiting at a level of about 1.5 times the normal plasma testosterone levels. Libido and potency are persistent under pure antiandrogen monotherapy. This phenomenon seems to be due to the maintenance of normal or elevated testosterone levels. Flutamide, nilutamide, and bicalutamide belong to that chemical family.
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 day seems to be required for monotherapy. In contrast to flutamide and nilutamide, bicalutamide therapy appears not to be associated with notable side effects [16]. Nether less, fulminate hepatic failures has been reported [1719]. Rationale for antiandrogens monotherapy. Today, available data seem not to reveal a clinically relevant advantage of any effective endocrine regimen and of endocrine treatment in general in overall survival. Endocrine treatment is thus pure palliative treatment. For that reason, quality of live under endocrine treatment must be seriously considered. Some side effects of classical surgical castration could be partially avoided by non classical castration: delayed or intermittent treatment, antiandrogen monotherapy. Antiandrogen monotherapy could be an alternative therapeutic option 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) demonstrated that cyproterone acetate in monotherapy (300 mg weekly administered by intramuscular injection) 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; M0M1. They noticed no difference in complete or partial remission, in local tumor mass reduction, in the incidence of side effects and complications between the three arms [21]. Moffat in 1990 compared goseriline monotherapy (3.6 mg per month) versus cyproterone acetate 300 mg per day in M+ or T3T4 patients and found a shorter median survival median time in patients receiving cyproterone acetate [22]. Thorpe et al (1996) compared goseriline acetate plus goseriline in a series of 525 patients (96% were M+). There was no statistically significant difference in terms of median time to progression between the goseriline plus cyproterone acetate arm and either monotherapy arm. But there was a statistically significant difference with goseriline
Experimental Oncology 26, 185-191, 2004 (September)
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acetate. That result could be explained by the experimental evidence that cyproterone acetate might be converted in the human body into a weak androgen [23]. Flutamide. Lund and Rasmussen published in 1988 the results of a prospective randomized study comparing flutamide 750 mg per day versus estrogens (DES 3 mg per day) in 40 patients with advanced disease. The authors found no statistically significant difference between the two arms in terms of response. Treatment with stilboestrol caused more frequent and more severe side effects than flutamide [24]. Delaere and Van in 1991 treated 40 patients with advanced disease by administration of flutamide (750 mg per day). They noticed that flutamide is effective but the follow-up is too short to assess weather time to progression and survival rate are comparable with those of conventional hormone therapy [25]. Chang et al published in 1996 a study of 92 patients with D2 disease randomized in two therapeutic arms: flutamide 750 mg per day or estrogens (DES 3 mg per day). Estrogens therapy caused more serious cardiovascular or thromboembolic complications than flutamide [2628]. This drug was not as active as estrogens [29]. Boccon-Gibod et al (1997) studied 104 patients M+ randomized to receive flutamide 750 mg per day or surgical castration. The authors noticed that flutamide could be a reasonable alternative to orchidectomy in highly selected patients [30]. Oosterling et al (1996) compared monotherapy with flutamide with MAB (maximal androgen blockade = orchidectomy + flutamide or administration of LH-RH agonists + flutamide) in a series of 905 patients with locally advanced or metastatic disease. The conclusions of this study were that flutamide represented a valid therapeutic option for sexually active prostatic cancer patients wishing to preserve their potency [31]. A clinical study (EORTC protocol 30892 compares flutamide versus cyproterone acetate as monotherapy in M1 disease), has shown no difference in either sexual activity or libido between patients treated with either cyproterone acetate (300 mg/day) or flutamide (250 mg/day), with 40% of patients on both forms of therapy (Table), maintaining potency [5]. At this time, no difference is seen in the results in terms of time to progression. Side effects are significantly more frequent with flutamide. Sexual activity seems to decrease equally in the two arms of the study [32]. Nitulamide. Studies concerning nilutamide are not numerous and the drug is not recommended by its manufacturer for use in monotherapy. Decensi et al (1991) treated 26 patients with metastatic carcinoma of the prostate by administration of nilutamide as a single agent. In this study, objective response rate was 7DEOH (257& IOXWDPLGH YHUVXV F\SURWHURQH DFHWDWH LQ JRRG SURJQRVLV0SURVWDWLFFDQFHU6H[XDODFWLYLW\DQGOLELGR )OXWDPLGH &\SURWHURQHDFHWDWH 3DUDPHWHUV 1XPEHU 1XPEHU 0RUQLQJHUHFWLRQV 6H[XDOUHVSRQVH (UHFWLRQZLWKUHVSRQVH 2UJDVP (MDFXODWLRQ
187 only 38.5% and median progression free survival and median survival were 9 and 23 months respectively. The tolerance of this agent was acceptable [33]. Classical nilutamide side effects are loss of adaptation to alcohol intolerance, nausea, darkness e.g. [34]. Bicalutamide. This drug has been investigated in monotherapy at dosage of 50, 150 or more mg per day [3538]. Tyrell in 1994 used bicalutamide 50 mg once daily in a monotherapy protocol on 267 patients with advanced prostate cancer. He observed breast tenderness in 63.4%, breast swelling in 52.5% and hotflushes in 23.5%. Partial regression was observed in 55.5% of the patients, stable disease in 15.6% and progression in 17.1% [39]. Chatelain et al (1994) reported French multicentric trial comparing bicalutamide monotherapy with surgical castration + nilutamide. In the bicalutamide group, only 6 patients withdrew because of adverse events as compared with 13 in the combined treatment group [40]. Verhelst et al (1994) studied the endocrine profiles in patients with prostate cancer treated by administration of bicalutamide as monotherapy (150 mg per day). The authors found an increase in LH and testosterone levels with an excellent androgen blockade [41]. In 1996 several authors (Solowan et al, Kolvenbag et al, Iversen et al, and Bales et al) reported in their series that monotherapy with 50 mg per day appeared to be inferior to surgical orchidectomy. The authors proposed further randomized studies with higher doses [11, 4247]. Iversen et al (1994 and 1998) and Anderson et al (1998) reported their results concerning monotherapy with bicalutamide 150 mg per day. On patients with M0 disease, the agent is equivalent to castration in terms of patients survival. In M1 disease, the bicalutamide monotherapy showed a shortfall in terms of survival with a difference in median survival of 42 days. In quality of life evolution, monotherapy showed a benefit in 2 domains concerning M0 disease and in 1 concerning M1 disease. No advantages for castration in any of the quality of life domains was observed) M0 or M1 patients) [48, 49]. Discussion. The studies of Huggins and collegues [5052] were reported six decades ago and contributed in our understanding of the prostate gland cancer and its treatment by endocrine therapy, retained some degree of androgen dependence. Furthermore, in prepubertally castrated male did not develop the prostatic cancer suggesting an implication of androgens in the pathogenesis of the disease [53]. Although references in the literature about the use of orchidectomy for the treatment of the enlarged prostate provided the scientific basis for the use of endocrine therapy based on the removal of the source of circulating plasma testosterone, either by bilateral orchidectomy, subcapsular orchidectomy or by the administration of estrogens, as the primary treatment for the management of metastatic advanced prostate cancer [54, 55, 56]. Synthesis of the estrogen, diethylstilboestrol (DES) (Dodds et al, 1938) was timely, thereby providing the first orally active agent for the treatment of the prostate cancer [57]. DES, which exercises its therapeutic result by inhibiting the release of luteinising hormone from
188 the pituitary gland and consequently, the synthesis and secretion of testosterone by the testes became the most generally accepted estrogen for the management of the advanced disease. The endocrine therapy is only palliative. The administration of DES, although effective and inexpensive, was not without controversy and several studies directed attention to the potentially dose-related side effects, such as cardiovascular problems, decreased libido, gynecomastia, gastric disturbances and nausea [5861]. At a dose of 3 mg/day DES was associated with thromboembolic and cardiovascular complications in nearly 30% of patients; but the parenteral administration of estrogen may offer a lower risk than an oral dosage [62]. On the other hand and on the basis of either removing the source of circulating testosterone, or restraining the intraprostatic biological action of 5a-dihydrotestosterone (DHT), new therapeutic improvements were developed, although few drugs other than DES, gained worldwide approval (Fig. 3).
Fig. 3. Endocrine therapy for advanced disease
The natural course of the prostate cancer follows a consistent biological process characterized by an unusually slow, although generally constant rate of growth [63, 64]. This rate of development can be improved by genetic instability of the cancer, and however, that the clinical stage and tumor grade, influence the outcome and the management [65]. The ultimate survival time depends on the prognostic factors present at initial diagnosis and 50% of patients die of their disease, the remaining 50% die with the disease in various stages of progression. The studies of Huggins claimed no more than a decline in the level of serum phosphatases and an associated relief of pain in patients with symptomatic disseminated disease, treated by androgen [51]. It is well known in ours days that the regulation of prostatic development is a most complicated biological process with cellular homeostasis sustained through of the equilibrium between growth stimulating and restraining factors which control cellular proliferation and apoptosis. This process is under the modulating influence of intraprostatic DHT [6668]. The DHT is important with regard to the androgenic action it exercises on the genome through its association with the androgen receptor, like a DHT-AR complex [69, 70]. Moreover, androgen withdrawal therapy can lead to a decline in the serum levels of prostate specific antigen (PSA) by about 90% [71].
Experimental Oncology 26, 185-191, 2004 (September) One of the main advantages of pure antiandrogen monotherapy is the maintenance of libido and potency. Is it justified to maintain libido and potency at the price of other and more troublesome side effects or even more at the price of earlier progression of the disease? Firstly, the question whether antiandrogen monotherapy is equally effective to other forms of classical androgen deprivation is not completely resolved. The best hormonal treatment for prostate cancer must be defined. Surgical orchidectomy is still considered as the gold standard of endocrine treatment of the disease, but data now available seem to demonstrate a little advantage, if any, to maximal androgen blockade, especially in patients with minimal disease. The results of antiandrogen monotherapy are such patients would eventually be compared with MAB results. Cyproterone acetate has been compared with estrogens and seems to be equally effective in major end points but, when compared with gosereline or gosereline plus cyproterone acetate, cyproterone acetate alone seems to be slightly less effective. Flutamide monotherapy compared in limited studies with MAB, administration of estrogens 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 testosterone and in the other hand, the use of pure antiandrogens 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 basically can [13]. The clinical data about antiandrogens in monotherapy seem to demonstrate that these remarks are not clinically significant. Secondly, the antiandrogen side effects are not negligible. In a review of different studies about flutamide, bicalutamide and nilutamide, Dole and Holdsworth (1997), concluded that nilutamide was somewhat inferior to both flutamide and bicalutamide with regard of side effects. Flutamide side effects are well defined: diarrhea (20%), gynecomastia (45%), hot flushes (2.5%), liver damages with increased levels of plasma aminotransferases (2.5%), nausea and vomiting (5%), and vertigo (2.5%). Bicalutamide is associated with less gastrointestinal effects than the flutamide and is not associated with pneumonitis, alcohol intolerance, or ocular defects which have been seen with the administration of nilutamide. Nevertheless, major hepatic disturbances have been reported with bicalutamide. The use of cyproterone acetate leads in most of the cases but not in all, to loss of libido and potency. Gynecomastia in association with administration of cyproterone acetate is not significant. The most extensive study of cardiovascular side effects has been carried out by the EORTC-GU group and reported by De Voogt in 1992. According to the data of this study, cyproterone acetate seems to be associated with a low percentage of cardio-vascular side effects. Hinkel in 1996 reported the observation about hepatic toxicity in
Experimental Oncology 26, 185-191, 2004 (September) patients treated by cyproterone acetate for 4 years (50 mg per day); it appeared in his conclusions that cyproterone acetate treatment might not favor the emergence of liver carcinomas in such patients. Libido and potency is preserved in more than 60% of the patients treated with flutamide or bicalutamide. In contrast, libido and potency are not maintained with cyproterone acetate treatment. Nevertheless, Schroder in 1997 reported the results of the EORTC protocol 30892 which compared cyproterone acetate versus flutamide: sexual activity decreased equally in both arms. Antiandrogen monotherapy option to preserve sexual potency concerns only the patients potent before treatment. The proportion of potent patients at the entry of most studies is somewhat variable (30% or more) and has not been always assessed. Preserving potency must be compared with side effects in that option, new andiandrogen drugs with fewer side effects are of great interest. Thirdly, compliance with hormonal therapy for prostate cancer is an important factor in such chronic illness [72]. Compliance may be affected by the drug side-effects but also by the schedule of administration. Obviously, some patients are reluctant to take a drug three times daily or once per day and prefer on administration per month or every three months. Fourthly, the cost-benefit of that treatment must be considered especially in that economic and financial period. In this point of view, antiandrogen monotherapy seems not to be the gold standard treatment for advanced prostate cancer. Alternatives therapeutic approaches for the treatment of advanced prostate cancer are in progress [73]. The metanalysis of accumulating data to allow appropriate clinical guidelines for the treatment of prostatic cancer is very important [74]. Overall, the analysis indicated that where MAB is to be used, a non-steroidal antiandrogen such as bicalutamide, or flutamide, was preferable to steroidal agents such as cyproterone acetate. An Italian randomized study showed no difference in survival between highdose (150 mg/day) bicalutamide and MAB therapy [75]. Other studies indicated that bicalutamide provides a similar survival outcome to castration in previously untreated patients with nonmetastatic advanced prostatic cancer and moreover, confers statistically significant health benefits with respect to sexuality and various physical parameters in relation to a patients quality of life [7678]. Conclusions. Antiandrogen monotherapy in the treatment of advanced prostate cancer could be a valid therapeutic option for the well informed patient motivated to maintain his potency. Further studies are required to definitely assess the efficacy of that therapeutic option in terms of survival and time to progression of the illness. Antiandrogen monotherapy side effects have been reported (gastro-intestinal, hepatic e.g.); new agents with less side effects and with longer half life (one administration par day) will certainly improve the use of that palliative treatment in advanced prostate cancer. Patients must be treated with attention on the new and exciting therapies and particularly on their quality of life. All scientists must continue to collaborate for the benefit of patients.
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ÌÎÍÎÒÅÐÀÏÈß ÏÐÎÃÐÅÑÑÈÐÓÞÙÅÃÎ ÐÀÊÀ ÏÐÅÄÑÒÀÒÅËÜÍÎÉ ÆÅËÅÇÛ: ÎÁÇÎÐ 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 ò.ä.). 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. Copyright © Experimental Oncology, 2004
