Hormonotherapy of advanced prostate cancer

Transcription

1 Annals of Oncology 16 (Supplement 4): iv80 iv84, 2005 doi: /annonc/mdi913 Hormonotherapy of advanced prostate cancer P. Pronzato & M. Rondini Department of Oncology, Felettino Hospital, La Spezia, Italy Introduction More than two decades of studies on hormonal treatment of Prostate Cancer are briefly reviewed. Recent American Society of Clinical Oncology recommendations have pointed the major issues faced in randomized clinical trials and meta-analyses. Androgen ablation remains the mainstay of treatment for advanced stages, while Docetaxel based chemotherapy is becoming the standard in hormonorefractory tumors and targeted therapies are approaching. Key words: prostate cancer, metastatic, hormonotherapy Prostate Cancer is the most common cancer among men of Western countries; it is a classical model of hormone dependent growth and the androgen ablation is a major treatment. The strategy of early stages is based on surgery (Radical Prostatectomy) or radiotherapy (External Beam or Brachytherapy) and a hormonal approach is frequently included mainly in association with Radiotherapy. Hormonotherapy is widely employed for treatment of advanced Prostate Cancer [1] since late 19th century, when castration was reported able to produce regression of prostatic hypertrophy. In mid twentieth century androgen deprivation by orchiectomy or high doses of estrogens assumed an established role in the strategy of treatment of advanced Prostate Cancer. The key point of hormonotherapy in Prostate Cancer is the ablation of the androgen action, i.e. the suppression of androgen production at the sites of synthesis or the androgen blockade at the target cell level. The testicles produce about the 90% of Testosterone under the control the Anterior Pituitary by Gonadotropins, while the remaining 10% is synthesized by conversion of adrenal precursors. Testosterone is converted at the target cell in the active compound Dihydrotestosterone. In a proportion of prostate tumors resistance to hormonotherapy develops as a result of the achievement of an androgen independent growth. The reasons of this development of resistance may regard the overexpression of the anti-apoptotic protein bcl-2, the mutation of the tumor suppressor gene p53 or others; so that some attempts may be explored to restore hormonosensitivity by modulating for instance the bcl-2 expression by differentiating agents like retinoids or interferons [2]. Hormonotherapy of Prostate Cancer The first hormonal treatment applied in Prostate Cancer was the surgical gonadal ablation. The orchiectomy was compared to placebo in a historical randomized study of the Veterans Administration Cooperative Urological Research Group (VACURG), in which a one-year and a five-year survival advantage was demonstrated for the surgical procedure (73% versus 66% and 35% versus 20%, respectively) [3]. The orchiectomy is now substituted by the employment of the so called LHRH agonists. These drugs currently administered in the depot formulations (monthly or three-monthly) cause downregulation of receptors in the anterior Pituitary (physiologically maintained by the pulsatile stimulation) and consequently inhibition of LH and FSH secretion of the Pituitary. Randomized trials have shown that both surgical and chemical androgen ablation have a similar impact on survival in patients with stage IV Prostate Cancer [4]. Choice between the two modalities may be based on the preference for a non surgical procedure, the absence of the so called flare phenomenon in the case of orchiectomy, convenience and costs; nevertheless, it should be considered that the flare can be controlled also with the association of an anti-androgen and that the surgery has not been demonstrate worse regarding Quality of Life or sexual aspects: for instance the patients in treatment with LHRH agonists more frequently perceive to be not free of cancer, because of the constant need of injections [5]. Cyproterone Acetate is a steroidal progestin blocking the interaction between testosterone and its receptor and inhibiting the Gonadotropins secretion. Flutamide, Nilutamide and Bicalutamide are non steroidal anti-androgens interfering with the interaction between the androgen receptors and the two main androgens, Testosterone and Dihydrotestosterone. Non steroidal anti-androgens do not show the relevant rate of cardiovascular side effects observed with Cyproterone but are not considered as effective as LHRH agonists. Since the synthesis of the adrenal androgens is not under control of the Hypothalamus Anterior Pituitary axis, LHRH agonists therapy or orchiectomy do not result in a total suppression of androgens. This consideration represents the basis of the so called Complete Androgen Blockade, based on q 2005 European Society for Medical Oncology

2 the association of the LHRH analog and an anti-androgen. This approach has been intensively studied in the last two decades, beginning from the first trial published in 1989 and showing a survival advantage with the Complete Blockade over the LHRH analog monotherapy [6]. In this double-blind, placebo-controlled trial the median overall survival was 35 versus 28 months, respectively and the benefit seemed to be greater in patients with minimal disease and a good Performance Status. These results have not been replied in other trials and a small advantage is seen also in the meta-analyses. The Prostate Cancer Trialists Group included in a meta-analysis [7] 27 trials and more than 8000 patients regarding Complete Androgen Blockade versus monotherapy with Cyproterone or a steroidal anti-androgen. The difference observed is small (absolute 1 2%) and not statistically significant; but the analysis conducted, excluding the data concerning the trials with Cyproterone, has shown a statistically significant survival advantage for the association of a LHRH analog and a nonsteroidal anti-androgen, possibly deriving from the superior antitumor activity and the avoidance of the non cancer related deaths observed in the Cyproterone arms. Nevertheless, the advantage remains small with a 2 3% improvement. Hormonotherapy of advanced stages Androgen ablation is currently the most important approach for metastatic prostate cancer. Recently the American Society of Clinical Oncology has published a series of recommendations for the initial hormonal management of androgensensitive metastatic, recurrent or progressive prostate cancer [8]. They address to important questions regarding the treatment strategy: what are the initial treatment options; whether anti-androgens are as effective as the castration therapies; whether the combined androgen blockade is better than castration alone; whether an early androgen deprivation is able to improve the outcome over a deferred therapy; whether an intermittent androgen deprivation may be better than the continuous deprivation therapy. Therefore, the items addressed by the panel regard basically the type of first line hormonotherapy and its timing. As outlined above, bilateral orchiectomy has been largely employed in the past basing on the results of randomized trials showing superiority over placebo and its problems consist in a limited risk of surgical complications and in the emotional impact on patients, even if in a study negative effects on sexual functioning are reported more frequently with LHRH analogs than with orchiectomy [5]. LHRH analogs or agonists have ousted orchiectomy in the clinical practice: a series of trials and a meta-analysis showed superimposable results in terms of Overall Survival or Time to Progression with respect to orchiectomy or estrogens [9]. The effect of LRHH agonists implies testosterone levels in the castration range in a month after first administration, but the first two weeks are characterized by a rise in LH and serum testosterone, rarely cause of the so called flare of disease. The endocrine effects of a long term administration of a iv81 LHRH agonist are partially reversible, not in terms of testosterone serum levels but concerning the castration symptoms, that may resume some months after discontinuation of the LHRH agonist. These last observations have represented the bases of two modalities aimed to counteract a possible tumor flare and to limit the side effects of treatment, respectively, namely the association to the LHRH agonist of an anti-androgen for a short initial period and the application of therapy intermittently. The association between LHRH agonist and anti-androgens has not systematically been studied outside the trials on Complete Androgen Blockade (that regard the maintenance of the association over the initial treatment period); nevertheless, the rise of LH and Testosterone is certainly turned off by the association and the procedure is common in the clinical practice mainly in the cases in which a rapid tumor progression is dreadful (urinary obstruction, spinal compression, hypercalcemia). The intermittent androgen deprivation may theoretically result in a better outcome both for the reduction in side effects, and for the postponement of the development of hormone resistance; nevertheless, randomized clinical trials comparing continuous versus intermittent androgen ablation are not so far available. From the limited data it may only be concluded that patients suspending the LHRH agonist and resuming it after an interval (basing on symptoms, or PSA rise, or Testosterone rise) are able again to respond in the 90% of the cases [10]. As a matter of fact, the most relevant clinical problem is the choice between the LHRH agonist, the Complete Androgen Blockade and a nonsteroidal anti-androgen. As mentioned above the Complete Androgen Blockade has a small but significant advantage over LHRH agonist alone and the best evidence derives from a meta-analysis carried out on individualized data of patients having entered the trials [7]. Specifically, the reduction in mortality for all trials was of borderline statistical significance, but a sensitivity analysis including the trials with nonsteroidal anti-androgens and excluding those with Cyproterone Acetate suggested a reduction in 5-year mortality from 75.3% with the LHRH agonist alone to 72.4% with the Complete Androgen Blockade (absolute risk reduction of 2.9%; P <0.05). Notably, one important randomized study of Complete Androgen Blockade, with or without Flutamide, was not included in this important meta-analysis and did not show any difference in survival [11]; nevertheless, in another less accurate metaanalysis (based on literature reports and not on individual data) also this trial was included and the advantage for Complete Androgen Blockade is again seen [12]. The eventual small superiority in terms of survival has to be balanced with the side effects of the anti-androgens; for what concerns the nonsteroidal anti-androgens (the steroidal being no more employed in the Complete Blockade), it has been observed a higher incidence of abdominal pain, diarrhea, opthalmological problems, anemia. The third option for the initial endocrine treatment of prostate cancer is the employment of a nonsteroidal antiandrogen alone. In general, anti-androgens produce equivalent

3 iv82 results in terms of Overall Survival, as seen in the literature meta-analysis by Seidenfeld [12]. Quality of Life has been studied in part of the patients entering randomized trials of LHRH agonists versus anti-androgens and the anti-androgens seem to be endowed with a more favourable toxicological profile, mainly for what concerns libido and physical capacity, as a consequence of the lack of inhibition for LH and Testosterone secretion. Some concerns derive from the observation that anti-androgens result in a shorter time to progression in some trials. The American Society of Clinical Oncology, for what regards the choice between the three options (Complete Androgen Blockade, LHRH agonist or anti-androgen alone) reasonably recommend the medical castration with a LHRH agonist (as an alternative to surgical castration) is to be considered firstly; the monotherapy with a nonsteroidal antiandrogen should be considered an alternative, basing on the preference of the patient with respect to his sexual life and the Complete Androgen Blockade should be considered discussing the patient the small potential gain in Survival and the additional toxic effects. A further item to address is the timing of hormonotherapy in the advanced stages and therefore leaving out of consideration the application in the adjuvant setting (i.e. in absence of signs of disease). In a systematic Cochrane review [13] four randomized trials comparing early versus deferred hormonotherapy in men with advanced Prostate Cancer have been considered; in these studies the treatment was postponed in the control group when patients became symptomatic. A small but statistically significant 10-year Survival advantage has been noted and obviously a high difference in Progression Free Survival has been seen in favour of the early treatment. Nevertheless the American Society of Clinical Oncology panel recommend just to discuss with the patient the pros and cons of early versus deferred therapy. The new scenario For many decades the medical treatment of Prostate Cancer has consisted exclusively of the hormonal treatment of advanced stages. Now the scenario is changing on the basis of the following facts: (i) many patients at risk are treated with hormonotherapy as an adjuvant to local treatments at early stages of disease; (ii) recent results show that the anti-androgen bicalutamide [14] given at the dose of 150 mg daily reduces the risk of disease progression in patients with localized or locally advanced Prostate Cancer in addition to standard care (radical prostatectomy) (iii) radiotherapy; (iv) watchful waiting; (v) the trials of the north-american group RTOG that the addition of Complete Androgen Blockade two months prior and two months during radiation prolong local control and Survival (RTOG 86 10) and that the addition of Complete Androgen Blockade for 24 months after radiotherapy (plus the Complete Androgen Blockade two months prior and during radiation) is of benefit in terms of Survival (RTOG 92 02) [15]. Chemotherapy based on Docetaxel and Prednisone or Docetaxel and Extramustine prolongs survival in patients with hormone-refractory prostate cancer with respect to the traditional combination of Mitoxantrone and prednisone, able only to palliate symptoms [16 17]. The key point is that the chemotherapy should be applied as soon as the hormonoresistance has developed and any type of hormonal manipulation has become useless without delaying a treatment potentially able to prolong survival, but requiring general conditions consistent with the weight of a myelotoxic chemotherapy. If Docetaxel should be hopefully administered before deterioration of Performance Status has occurred, on the other hand a full exploitation of hormonotherapy is appropriate until the eventual benefit derived from bringing forward chemotherapy has been demonstrated. In this context it is particularly important defining the role of the so called second line hormonotherapy. When a progression occurs under a first line hormonal treatment, the clinical decision should take into consideration the type of hormonal treatment applied (LHRH agonist, Complete Androgen Blockade, anti-androgen monotherapy): in other words, does a progression under a single hormonal agent (LHRH agonist or anti-androgen) really correspond to the development of androgen independency? And, more in general, also in the cases in which a Complete Androgen Blockade has been applied a different type of hormonal manipulation is potentially useful? When a patient being given LHRH agonist alone undergoes progression, the late addition of an anti-androgen may result in biochemical and objective responses [1]. In the case of patients taking the anti-androgen alone the addition of the LHRH agonist is appealing considering the superiority at least in terms of Time to progression of Complete Androgen Blockade over monotherapy, but clinical results are not available. Basing on these premises, patients with tumors becoming hormonoresistent are usually in treatment with anti-androgens. Anedoctical reports regard observation of response to nonsteroidal agents in patients in progression under a steroidal agent and viceversa and response to a newer nonsteroidal agent when another has been employed (for instance Bicalutamide after Flutamide). Moreover, responses are observed with the withdrawal of the nonsteroidal anti-androgen. This phenomenon is not completely understood and may be due to a mutation in the androgen receptor becoming sensitive to the drug behaving as an activator rather as an inhibitor. The response with the antiandrogen withdrawal is about 30% and of short duration [18]. The progression after anti-androgen withdrawal may not correspond to a complete hormono-independency. The persistence of clones sensitive to androgens may justify a further hormonal approach based on the suppression of androgens produced by the adrenals (about 10%) and not blocked by the primary manipulations focused on the suppression of the Hypothalamus Anterior Pituitary Testicle axis. Again small studies report responses with different compounds able to interfere with the adrenal androgen production like Hydrocortisone

4 Acetate or Aminoglutethimide, but the good result are not replied in the large randomized trials and have to be ascribed to selection biases [19]. Two main randomized trials focus on the second line hormonotherapy. In the first [20], Suramine, a drug thought to interfere with growth factors pathway, was compared with Hydrocortisone Acetate at the dose of 40 mg daily and a biochemical response (PSA decline of 50% or more) was observed with the steroid alone. More recently the Cancer and Leukemia Group B reported the results of the comparison between the anti-androgen withdrawal and the anti-androgen withdrawal plus Ketoconazole and Hydrocortisone Acetate [21]. The latter is also a powerful suppressor of extragonadal androgenesis, acting through the inhibition of cytochrome P450 14a-demethylase, an enzyme involved in the conversion of lanosterol to cholesterol. In this trial the anti-androgen withdrawal resulted in 11% of PSA response, with respect to the 27% of the association with Ketoconazole and corticosteroid, without difference in Overall Survival. Interestingly, the application of Ketoconazole and Hydrocortisone in the patients initially treated with withdrawal alone resulted in 32% of biochemical response. The median Time to PSA Progression was months in patients responding. Conclusion In spite of the achievements of chemotherapy, the ablation of androgen action remains the mainstay of treatment for advanced Prostate Cancer. Results of trials and meta-analyses carried in more than two decades have pointed that three modalities may be considered as initial first line treatment: the LHRH agonists that have replaced orchiectomy, the Complete Androgen Blockade (with limited survival advantage to be balanced with the heavier toxicity) and the nonsteroidal antiandrogen monotherapy (with a better profile concerning sexual life). When progression occurs, the anti-androgen withdrawal is reasonable and following progression after the withdrawal the suppression of androgens of adrenal origin may be attempted. Both modalities achieve responses in a minority of cases and the duration of response or stabilization is usually short. Since a relevant benefit may be offered to patients failing the first line hormonotherapy with application of Docetaxel based chemotherapy, the clinical decision at the time of first line hormonotherapy progression should consider the limitations of second lines hormonotherapy and the need to avoid the deterioration of general conditions rendering inapplicable an aggressive chemotherapy. 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