160S139 © 1990 S. Karger AG, Basel 0302-2838/90/0181 -0010$2.75/0
Eur Urol 1990;18:10-15
Advanced Prostatic Cancer: Clinical and Hormonal Response to Flutamide in Patients Pretreated with LHRH Analogue and Cyproterone Acetate F. DiSilverio, F. Sciarra, G. D’Eramo Institute of Urology, V Clinica Medica, University of Rome ‘La Sapienza’, Italy
Key Words. Prostatic cancer • LHRH analogue • Cyproterone acetate • Flutamide Abstract. The aim of the present investigation was to establish whether in advanced prostatic carcinoma in relapse treated with LHRH analogues combined with cyproterone acetate (CPA), substitution of this antiandrogen with another compound such as flutamide (FLU) might lead to further subjective and objective improvement. The present randomized study was carried out on 100 patients in relapse treated with long acting LHRH analogue + CPA: 52 patients were submitted to combination therapy with FLU, whilst the remaining 48 cases continued with CPA treatment. Plasma levels of gonadotropin FSH-LH, androstenedione and dehydroepiandrosterone sulphate were significantly reduced by both treatments, testosterone fell to castration values, but prolactin showed no change. Progress of the disease was confirmed in all the patients who continued with CPA treatment with a median survival rate of 9.3 ± 2 months from the start of the second cycle of CPA. In the FLU-treated group, the overall objective response differed significantly in relation to the stage of the disease. In fact, in stage D2, the response was poor with a median survival of 12 ± 2 months, which is almost comparable to that in the CPA group. In stage D1, a clinical improvement, even if of short duration, was observed in almost 50% of the cases with a median survival of 18 ± 3 months. Good results were also obtained in undifferentiated tumours, FLU probably acting as an antimitotic agent. Moreover, FLU also exerted an analgesic effect, with relief of bone pain in 65% of the cases in stage D2. In conclusion, in advanced prostatic adenocarcinoma, CPA may be used as first line therapy in combination with surgical or medical castration to suppress adrenal androgens. As second line therapy, FLU may be recommended for patients in stage D1 in relapse after other conventional hormonal treatments, providing additional benefits even if of short duration.
Advanced prostatic carcinoma responds to androgen withdrawal therapy with a symptomatic improvement in more than 70% of the cases [1-7], Bilateral orchiectomy or treatment with LHRH analogues produce a 95 % reduc tion in testosterone (T) production and a 50% decrease in prostatic dihydrotestosterone (DHT) concentrations [6, 8], The residual androgens of adrenal origin may be neu-
tralized by combining medical or surgical castration with antiandrogens, such as cyproterone acetate (CPA), flu tamide (FLU), megestrol acetate, anandron, kétocon azole and aminoglutéthimide. The best results are ob tained when the antiandrogen is given immediately after surgery or combined with LHRH analogues, and not later when the disease is in progression [9, 10]: relapse gener ally occurs within 12-30 months and patients rarely respond favourably to further endocrine therapies. Downloaded by: University of Exeter 144.173.6.94 - 5/4/2020 7:56:27 AM
Introduction
11
Flutamide in Pretreated Prostatic Cancer
Materials and Methods A series of 100 patients aged 53-78 years presenting stage C-D prostatic carcinoma were studied. All patients were submitted to treatment with LHRH analogue (Zoladex depot, 3.6 mg i.m. every 28 days) combined with CPA (200 mg/day). When relapse occurred after 12-30 months, all patients underwent a trial of 3 months before being considered non-responders: in 48 cases therapy with CPA was continued, whereas in the remaining 52 cases the drug was substituted by FLU (7 50 mg/day). Eligibility criteria for entry into this study were that each patient should have a life expectancy of at least 3 months from the time of entering the trial and had not previously received cytotoxic chemo therapy or estrogen treatment; patients with severe ureteric obstruc tion and/or spinal cord compression were also excluded. All patients were controlled every 3 months by means of clinical examination, X ray and bone scintigraphy, liver scan and evaluation of haematological and biochemical parameters such as prostatic acid phosphatase (PAP), alkaline phosphatase, plasma T, androstenedione (A), déhy droépiandrostérone sulphate (DHEAS), gonadotrophins (LH-FSH) and prolactin (PRL). Response to treatment was based on subjective and objective criteria. In the subjective assessment, a score from 0 to 3 was assigned to urological symptoms and from 0 to 4 to perfor mance status, bone pain and analgesia used. Only patients present ing a total pretreatment score (sum of the scores of individual parameters) of at least 4 were eligible. The subjective response to treatment was considered satisfactory when: (1) mean urological symptom score, performance status score, bone pain score and anal gesia score were not increased, (2) total subjective score decreased by 4, and (3) performance status score, bone pain score or analgesia score decreased by 2 and the mean urological symptom score decreased by 1.5.
In the objective assessment, the extent of the disease was evalu ated according to the protocol of the UICC: the primary tumour was examined by digital palpation and the prostatic volume by per-rectal ultrasound scanning, whereas bone:and other métastasés were evaluated by isotope bone scan, X-ray and clinical examination. Complete objective remission (COR) was obtained when no clinical, radiological, isotope bone scan or biochemical modifications were revealed. Partial objective regression (POR) was obtained when the primary tumour decreased by one or more ‘t’ categories, prostatic volume decreased by 35%, bone métastasés were decreased and serum PAP was reduced by 80% or more. Objective progression (PROGR) was considered when the primary tumour was increased by one or more ‘f categories, prostatic volume was increased by 35% or new métastasés appeared. Stable disease (SD) was deter mined when neither PROGR nor POR was demonstrated. Duration of the response was calculated from the onset of treat ment until evidence of disease progression. The mean duration of follow-up was 12 months for second cycle CPA-treated patients (range 1-18 months) and 24 months for FLU-treated patients (range 1-30 months). Flormones were determined in plasma samples taken at 8-9 a.m. before and after 6, 12, 18 and 24 months of treatment with LHRH analogue + CPA or FLU. Gonadotropin FSH-LFI, PRL, T, A, DFIEAS and PAP were determined by conventional RIA technique [12].
Results
Hormonal Response LHRH Analogue + CPA. Plasma LH and FSH values, with pretreatment levels of 18 ± (SE) 4 and 14 ± 3 mIU/ml, respectively, drop to 5-6 mIU/ml (p < 0.001) remaining low during the follow-up period as a conse quence of the combined inhibitory effect of the analogue and CPA on the hypothalamic-pituitary axis. Plasma PRL, with pretreatment values of 13 ± 3 ng/ml shows no significant change remaining within the upper limit of the normal range (fig. 1). Plasma T shows a dramatic drop from 4.5 ± 0.7 ng/ml before treatment to castration val ues of 0.4-0.5 ng/ml (p < 0.001), whilst plasma A shows a significant decrease from 1.3 ± 0.12 to 0.6-0.7 ng/ml (p < 0.001 ) during the 18-month follow-up period. Serum levels of DHEAS follow a similar pattern, with a signifi cant reduction from basal values of 1,180 ± 120 to 700 ng/ml (p < 0.05) during the treatment period (fig. 2). LHRH Analogue + FLU. Plasma LH, FSH and PRL concentrations during this combination therapy are not significantly different from those observed in patients treated with LHRH analogue + CPA: during the 24month of follow-up LH and FSH values range between 4-7 and 6-8 mIU/ml, respectively, and those of PRL between 9 and 12 ng/ml (fig. 1 ). T secretion is also inhib ited, with plasma levels of 0.5-0.7 ng/ml, comparable to Downloaded by: University of Exeter 144.173.6.94 - 5/4/2020 7:56:27 AM
Preliminary investigations carried out by Di Silverio et al. [9] have shown, however, that FLU may induce a subjective improvement and a further period of remis sion when relapse occurs in 17% of castrated patients treated with CPA; 35% of the patients show stabilization of the disease, whereas primary tumour size is reduced in 57% and bone pain regresses in 80% of the cases. Favourable response rate is also observed in undifferen tiated G3 tumours, probably because FLU acts not only by competing with androgens at receptor level, but also by means of postreceptor or antimitotic mechanisms [11], These findings, however, needed confirmation in a larger group of patients, with a longer follow-up period. In the present investigation, 100 patients with advanced prostatic carcinoma have been studied, 52 of whom were randomized to FLU therapy when relapse occurred dur ing LHRH analogue and CPA treatment. In the remain ing 48 cases, CPA treatment was repeated. The mean duration of follow-up was 39 months in patients treated with CPA and 24 months in patients treated with FLU.
Fig. 1. Plasma concentrations of gonadotropin LH, FSH and of PRL in patients with advanced prostatic cancer during long-term treatment with LHRH analogue combined with CPA or FLU.
Fig. 3. Changes in PAP concentrations in patients with advanced prostatic cancer during long-term treatment with LHRH analogue combined with CPA or FLU.
those found during treatment with LHRH analogue + CPA. A reduction is also observed in plasma A and DHEAS concentrations, but the values are higher than those found during the combination therapy with CPA: 0.80-1.1 and 800-870 ng/ml, respectively, during the whole period of treatment (fig. 2).
Di Silverio/Sciarra/D’Eramo
Fig. 2. Plasma concentrations of T, A and DHEAS in patients with advanced prostatic cancer during long-term treatment with LHRH analogue combined with CPA or FLU.
Clinical Response LHRH Analogue + CPA. The 48 patients with pros tatic carcinoma in relapse, who continued with CPA treatment, all in stage D1-D2 (7 Gl, 12 G2 and 29 G3), showed no objective or subjective improvement, re maining in progress. PAP was increased in all patients with values up to 122 ng/ml and remained elevated between 10 and 17 ng/ml during the second cycle of combination therapy (fig. 3). Twenty-nine patients died within 6 months, 14 within 1 year and the remaining 5 within 18 months from the start of the randomized treatment with CPA. Median survival in this group was 9.3 ± 2 months (fig. 4). LHRH Analogue +FLU. Of the 52 patients in relapse treated with FLU, all in stage D1-D2 (5 Gl, 18 G2 and 29 G3), 45 showed a subjective improvement according to the protocol criteria; in 26 patients with bone métas tasés bone pain showed complete regression in 11 and was substantially reduced in 5 cases, whilst in another 5 stabilization was observed (table 1). Median time to subjective response was 5 months in stage D1 and 1.8 months in stage D2. Regarding, the overall objective response rate in stage D1 prostatic carDownloaded by: University of Exeter 144.173.6.94 - 5/4/2020 7:56:27 AM
12
Flutamide in Pretreated Prostatic Cancer
13
Table 1. FLU effect on pain in stage D2 prostatic carcinoma Cases Improvement
Stabilization Worsening
from severe to absent from severe to moderate from moderate to absent
3 5 8 5 5
Discussion
cinoma, after 6 months of FLU treatment CR occurred in 4 patients (2 G2 and 2 G3), PR in 11 (2 G2 and 9 G3), SD in 10 (4 Gl, 4 G2 and 2 G3) and PROGR in 1 patient (G3), whereas in the stage D2 group, after 6 months treatment, no CR was observed, only 1 case (G3) being in PR and 16 in SD (1 Gl, 2 G2 and 13 G3). Eight cases remained in PROGR (6 G2 and 2 G3). Median time to objective response was 5 months in stage D1 and 3.6 months in stage D2. The highest response rate was observed at a local level, particularly in the primary prostatic tumour, whilst bone métastasés were the main site of progression. PAP levels, increased in all patients before FLU treatment, fell to mean values of 5 ± 1 ng/ml during FLU treatment and increased again to mean values of 9 ± 1.5 ng/ml when relapse occurred (fig. 3). Two patients died before 6 months, 15 died within 12 months, 12 within 18 months and 7 within 24 months. Median survival was 18 ± 2 months in stage D1 and 12 ± 2 months in stage D2 (fig. 4). The response rate was also positive in cases with G3 prostatic carcino ma: in fact, after 12 months of FLU treatment 1 patient was in CR, 7 were in PR and 10 in SD, and after 18 months 5 were still in PR and 6 in SD.
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Fig. 4. Survival rate in patients with stage D1 and D2 prostatic cancer treated with LHRH analogue combined with CPA or FLU.
Complete androgen inhibition in our patients with advanced prostatic carcinoma was obtained using a com bination therapy with an LHRH analogue and CPA given at the beginning of treatment, in order to eliminate the risk of disease flare-up, which may occur as a conse quence of the initial rise in plasma T. Adrenal androgens are also neutralized, with a reduction of 50% in plasma DHEAS and A, thus enhancing the action of the antian drogen at target tissue level: in fact, the concentrations of DHT in cancer tissue decrease to 1.5 ng/g tissue after castration alone and drop to 0.2 ng/g tissue with FLU [13]. Validity of the combination therapy is also demon strated experimentally by cancer tissue cultures, where very low androgen levels, comparable to those found after orchiectomy alone, stimulate cell growth [14], Moreover, the 20-30% of non-responders to surgical or medical castration alone may decrease to 10% as found by Labrie et al. [15]. Combination therapy with a long-acting LHRH ana logue + CPA used in the present investigation led to a clinical improvement in 70% of the cases with an in creased duration of remission-stabilization periods up to 12-30 months. Relapse of the disease occurs without sig nificant changes in the hormonal pattern, suggesting the development of androgen-insensitive tumour cells or the development of a population of hypersensitive cells growing in a very poor androgen milieu, as hypothesized by Labrie et al. [15]. According to the second hypothesis, substitution of CPA with a more potent pure antiandrogen, such as FLU, might provide additional benefits. It has been shown in fact that FLU is approximately twice as potent as CPA in inhibiting DHT action and 100% more effec tive in inhibiting DNA synthesis induced by testosterone propionate in the ventral prostate of castrated rats [16]. This compound was employed here as second line ther-
Di Silverio/Sciarra/D’Eramo
14
present series remission was observed after 6 months FLU therapy in 12 cases with G3 tumour, after 12 months in 9, after 18 months in 5 and after 24 months of FLU therapy in 2, whilst stabilization was found after 6, 12, 18 and 24 months FLU therapy in 15, 10, 6 and 5 cases, respectively. This interesting observation suggests that the effect of FLU in this instance may be non-hormonal, probably exerting an antimitotic action. Further investigations are needed to elucidate the mechanism of action of FLU other than that of receptor blockade. Moreover, it is important to underline that FLU also exerts an analgesic effect: in fact, relief of bone pain, even when the disease is in progress, has been observed in 65% of our patients in stage D2, suggesting that this effect is not mediated by a direct antitumoral action but probably through its phenacetin-like properties. In conclusion, in advanced prostatic carcinoma, CPA may be used as first line therapy in combination with surgical or medical castration, in order to neutralize the effects of adrenal androgens. Relapse, probably condi tioned by the prevalence of an androgen-resistant neo plastic cell population, may still be controlled by FLU, which is also effective in undifferentiated tumours, prob ably acting as an antimitotic drug on prostatic cancer cells, but not on distant métastasés. FLU therapy, how ever, may also be usefully employed in stage D2, since this compound possesses an analgesic effect.
References 1 Di Silverio, F.; Sciarra, F.: Therapeutic approaches in prostatic cancer. J. Steroid Biochem. 25: 773-779 (1986). 2 Nesbit, R.M.; Baum, W.C.: Endocrine control of prostatic carci noma: clinical and statistical survey of 1818 cases. JAMA 143: 1317-1320 (1950). 3 Jordan, W.B.; Blackard, C.E.; Byar, D.P.: Reconsideration of orchiectomy in the treatment of advanced prostatic carcinoma. Sth. med. J. 70: 1411-1413 (1977). 4 Mettelin, C.; Natarajan, N.; Murphy, G.P.: Recent patterns of care of prostatic cancer patients in the United States: results from the surveys of the American College of Surgeons Commis sion on Cancer. Int. Adv. Surg. Oncol. 3: 277-321 (1982). 5 Murphy, G.P.; Beckley, S.; Brady, M.F.; et al.: Treatment of newly diagnosed metastatic prostate cancer patients with che motherapy agents in combination with hormones versus hor mones alone. Cancer 51: 1264-1272 (1983). 6 Di Silverio, F.; Tenaglia, R.; Bigio, A.; et al.: Trattamento del carcinoma prostatico avanzato con un agonista dello LH.RH somministrato da solo o in combinazione con il ciproterone ace tato; in Motta, Serio, Terapia ormonale della patologia prostati ca: aspetti di base e clinici, pp. 74-87 (Medicom Europe, Am sterdam 1988). Downloaded by: University of Exeter 144.173.6.94 - 5/4/2020 7:56:27 AM
apy in 52 patients in relapse after treatment with LHRH analogue + CPA: the remaining 48 patients, also in relapse with the same treatment, but who continued with CPA therapy at the previous dosage, were considered as controls. The two groups were identical as far as mean age, stage distribution and histological grade was concerned. Progress of the disease was confirmed in all the patients who continued with CPA treatment: median survival was 9.3 + 2 months, ranging between 1 and 18 months, regardless of the histological grade. In the FLU-treated group, on the contrary, analysis of the overall objective response showed a significant difference (p < 0.05) in stage D1 when compared to stage D2. In fact, in stage D2 the response was poor and the survival rate (12 ± 2 months) was comparable to that of the CPA group, whilst in stage Dia clinical improvement was observed in approximately 50% of the cases, with a median sur vival of 18 ± 2 months. This clinical response was inde pendent of the hormonal pattern which was character ized by castration levels of plasma T, as seen in the CPA-treated group: moreover, the decrease in plasma concentrations of A and DHEAS was less pronounced in comparison with that observed during the previous treatment. Other investigators have reported a poor response to FLU after a first cycle of conventional hormonal thera py: Sogani et al. [ 17] observed a clinical improvement of short duration in 6 out of 26 patients who had become refractory to previous endocrine therapy, Johansson et al. [ 18] in almost all the patients studied and Stoliar and Albert [ 19] in 7 out of 15 patients. The survival rate was significantly higher when compared to patients treated with orchiectomy alone or estrogens, but no different to that obtained when orchiectomy was associated to estro gens or CPA. The present results in stage D2 patients confirm these findings, which may be partially explained by the fact that FLU exerts a particularly efficacious effect upon the prostatic tumour but not on distant métastasés. This observation is supported by the good results obtained in stage D1 patients with only locally advanced tumour. Furthermore, FLU may reduce the volume of the pri mary tumour also in those cases with distant métastasés in progression. From a theoretical point of view one would expect the best results to be obtained in more differentiated pros tatic carcinoma, such as G1-G2, with adequate andro gen receptor content. However, a good response rate is also reached in undifferentiated tumours: in fact, in the
Flutamide in Pretreated Prostatic Cancer
15 Labrie, F.; Dupont, A.; Cusan, L.; et al.: Combination therapy with flutamide and castration (LH.RH agonist or orchiectomy) in previously untreated patients with clinical stage D2 prostate cancer: today’s therapy of choice. J. Steroid Biochem. 30: 107— 117 (1988). 16 Poyet, P.; Labrie, F.: Comparison of the antiandrogenic-androgenic activities of flutamide, cyproterone acetate and megestrol acetate. Mol. cell. Endocrinol. 42: 283-288 (1985). 17 Sogany, P.C.; Vagaiwala, M.R.; Whitmore, W.F., Jr.: Experience with flutamide in patients with advanced prostatic cancer with out prior endocrine therapy. Cancer 54: 744-750 (1984). 18 Johansson, J.; Andersson, S.; Beckman, K.; et al.: Clinical eval uation of flutamide and estramustine as initial treatment of met astatic carcinoma of prostate. Urology 29: 55-59 (1987). 19 Stoliar, B.; Albert, P.J.: SCH 13521 in the treatment of advanced carcinoma of the prostate. J. Urol. Ill: 803-807 (1974).
Prof. Franco Di Silverio Clinica Urologica Università di Roma ‘La Sapienza’ Policlinico Umberto I Viale del Policlinico 1-00161 Rome (Italy)
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7 Di Silverio, F.; Sciarra, F.: Results of long-term treatment with cyproterone acetate (CPA) in advanced prostatic cancer pa tients; in Klosterhalfen, Endocrine management of prostatic cancer. New developments in biosciences, voi. 4, pp. 115-120 (De Gruyter, Berlin 1988). 8 Geller, J.; Albert, J.; Loza, D.; et al.: DHT concentrations in human prostatic cancer tissue. J. clin. Endocr. Metab. 46: 440453 (1978). 9 Di Silverio, F.; Sciarra, F.; Tenaglia, R.; et al.: Flutamide treat ment of stage D prostatic cancer patients; in Giuliani, Boccardo, Santi, New trends in diagnosis and treatment of prostatic cancer, pp. 167-171 (Acta Medica, Roma 1987). 10 Labrie, F.; Dupont, A.; Belanger, A.; et al.: Combination therapy with flutamide and castration (LH.RH agonist or orchiectomy) in advanced prostate cancer: a marked improvement in response and survival. J. Steroid Biochem. 23: 833-841 (1985). 11 Neri, R.; Kassem, N.: Biological and clinical properties of antiandrogens. Prog. Cancer Res. Ther. 31: 507-518 (1984). 12 Toscano, V.; Petrangeli, E.; Adamo, M.; et al.: Simultaneous determination of 5-alpha reduced metabolites of testosterone in human plasma. J. Steroid Biochem. 6: 575-578 (1981). 13 Labrie, F.; Luthy, L; Veilleux, R.; et al.: New concepts on the androgen sensitivity of prostate cancer; in Murphy, Proc. 2nd Int. Symp. Prostate Cancer, pp. 145-172 (Liss, New York 1987). 14 Labrie, F.; Veilleux, R.: A wide range of sensitivities to andro gens developed in cloned Shionogi mouse mammary tumor cells. Prostate 8: 293-300 (1986).
15
Eur Urol 1990;18:10-15
Advanced Prostatic Cancer: Clinical and Hormonal Response to Flutamide in Patients Pretreated with LHRH Analogue and Cyproterone Acetate F. DiSilverio, F. Sciarra, G. D’Eramo Institute of Urology, V Clinica Medica, University of Rome ‘La Sapienza’, Italy
Key Words. Prostatic cancer • LHRH analogue • Cyproterone acetate • Flutamide Abstract. The aim of the present investigation was to establish whether in advanced prostatic carcinoma in relapse treated with LHRH analogues combined with cyproterone acetate (CPA), substitution of this antiandrogen with another compound such as flutamide (FLU) might lead to further subjective and objective improvement. The present randomized study was carried out on 100 patients in relapse treated with long acting LHRH analogue + CPA: 52 patients were submitted to combination therapy with FLU, whilst the remaining 48 cases continued with CPA treatment. Plasma levels of gonadotropin FSH-LH, androstenedione and dehydroepiandrosterone sulphate were significantly reduced by both treatments, testosterone fell to castration values, but prolactin showed no change. Progress of the disease was confirmed in all the patients who continued with CPA treatment with a median survival rate of 9.3 ± 2 months from the start of the second cycle of CPA. In the FLU-treated group, the overall objective response differed significantly in relation to the stage of the disease. In fact, in stage D2, the response was poor with a median survival of 12 ± 2 months, which is almost comparable to that in the CPA group. In stage D1, a clinical improvement, even if of short duration, was observed in almost 50% of the cases with a median survival of 18 ± 3 months. Good results were also obtained in undifferentiated tumours, FLU probably acting as an antimitotic agent. Moreover, FLU also exerted an analgesic effect, with relief of bone pain in 65% of the cases in stage D2. In conclusion, in advanced prostatic adenocarcinoma, CPA may be used as first line therapy in combination with surgical or medical castration to suppress adrenal androgens. As second line therapy, FLU may be recommended for patients in stage D1 in relapse after other conventional hormonal treatments, providing additional benefits even if of short duration.
Advanced prostatic carcinoma responds to androgen withdrawal therapy with a symptomatic improvement in more than 70% of the cases [1-7], Bilateral orchiectomy or treatment with LHRH analogues produce a 95 % reduc tion in testosterone (T) production and a 50% decrease in prostatic dihydrotestosterone (DHT) concentrations [6, 8], The residual androgens of adrenal origin may be neu-
tralized by combining medical or surgical castration with antiandrogens, such as cyproterone acetate (CPA), flu tamide (FLU), megestrol acetate, anandron, kétocon azole and aminoglutéthimide. The best results are ob tained when the antiandrogen is given immediately after surgery or combined with LHRH analogues, and not later when the disease is in progression [9, 10]: relapse gener ally occurs within 12-30 months and patients rarely respond favourably to further endocrine therapies. Downloaded by: University of Exeter 144.173.6.94 - 5/4/2020 7:56:27 AM
Introduction
11
Flutamide in Pretreated Prostatic Cancer
Materials and Methods A series of 100 patients aged 53-78 years presenting stage C-D prostatic carcinoma were studied. All patients were submitted to treatment with LHRH analogue (Zoladex depot, 3.6 mg i.m. every 28 days) combined with CPA (200 mg/day). When relapse occurred after 12-30 months, all patients underwent a trial of 3 months before being considered non-responders: in 48 cases therapy with CPA was continued, whereas in the remaining 52 cases the drug was substituted by FLU (7 50 mg/day). Eligibility criteria for entry into this study were that each patient should have a life expectancy of at least 3 months from the time of entering the trial and had not previously received cytotoxic chemo therapy or estrogen treatment; patients with severe ureteric obstruc tion and/or spinal cord compression were also excluded. All patients were controlled every 3 months by means of clinical examination, X ray and bone scintigraphy, liver scan and evaluation of haematological and biochemical parameters such as prostatic acid phosphatase (PAP), alkaline phosphatase, plasma T, androstenedione (A), déhy droépiandrostérone sulphate (DHEAS), gonadotrophins (LH-FSH) and prolactin (PRL). Response to treatment was based on subjective and objective criteria. In the subjective assessment, a score from 0 to 3 was assigned to urological symptoms and from 0 to 4 to perfor mance status, bone pain and analgesia used. Only patients present ing a total pretreatment score (sum of the scores of individual parameters) of at least 4 were eligible. The subjective response to treatment was considered satisfactory when: (1) mean urological symptom score, performance status score, bone pain score and anal gesia score were not increased, (2) total subjective score decreased by 4, and (3) performance status score, bone pain score or analgesia score decreased by 2 and the mean urological symptom score decreased by 1.5.
In the objective assessment, the extent of the disease was evalu ated according to the protocol of the UICC: the primary tumour was examined by digital palpation and the prostatic volume by per-rectal ultrasound scanning, whereas bone:and other métastasés were evaluated by isotope bone scan, X-ray and clinical examination. Complete objective remission (COR) was obtained when no clinical, radiological, isotope bone scan or biochemical modifications were revealed. Partial objective regression (POR) was obtained when the primary tumour decreased by one or more ‘t’ categories, prostatic volume decreased by 35%, bone métastasés were decreased and serum PAP was reduced by 80% or more. Objective progression (PROGR) was considered when the primary tumour was increased by one or more ‘f categories, prostatic volume was increased by 35% or new métastasés appeared. Stable disease (SD) was deter mined when neither PROGR nor POR was demonstrated. Duration of the response was calculated from the onset of treat ment until evidence of disease progression. The mean duration of follow-up was 12 months for second cycle CPA-treated patients (range 1-18 months) and 24 months for FLU-treated patients (range 1-30 months). Flormones were determined in plasma samples taken at 8-9 a.m. before and after 6, 12, 18 and 24 months of treatment with LHRH analogue + CPA or FLU. Gonadotropin FSH-LFI, PRL, T, A, DFIEAS and PAP were determined by conventional RIA technique [12].
Results
Hormonal Response LHRH Analogue + CPA. Plasma LH and FSH values, with pretreatment levels of 18 ± (SE) 4 and 14 ± 3 mIU/ml, respectively, drop to 5-6 mIU/ml (p < 0.001) remaining low during the follow-up period as a conse quence of the combined inhibitory effect of the analogue and CPA on the hypothalamic-pituitary axis. Plasma PRL, with pretreatment values of 13 ± 3 ng/ml shows no significant change remaining within the upper limit of the normal range (fig. 1). Plasma T shows a dramatic drop from 4.5 ± 0.7 ng/ml before treatment to castration val ues of 0.4-0.5 ng/ml (p < 0.001), whilst plasma A shows a significant decrease from 1.3 ± 0.12 to 0.6-0.7 ng/ml (p < 0.001 ) during the 18-month follow-up period. Serum levels of DHEAS follow a similar pattern, with a signifi cant reduction from basal values of 1,180 ± 120 to 700 ng/ml (p < 0.05) during the treatment period (fig. 2). LHRH Analogue + FLU. Plasma LH, FSH and PRL concentrations during this combination therapy are not significantly different from those observed in patients treated with LHRH analogue + CPA: during the 24month of follow-up LH and FSH values range between 4-7 and 6-8 mIU/ml, respectively, and those of PRL between 9 and 12 ng/ml (fig. 1 ). T secretion is also inhib ited, with plasma levels of 0.5-0.7 ng/ml, comparable to Downloaded by: University of Exeter 144.173.6.94 - 5/4/2020 7:56:27 AM
Preliminary investigations carried out by Di Silverio et al. [9] have shown, however, that FLU may induce a subjective improvement and a further period of remis sion when relapse occurs in 17% of castrated patients treated with CPA; 35% of the patients show stabilization of the disease, whereas primary tumour size is reduced in 57% and bone pain regresses in 80% of the cases. Favourable response rate is also observed in undifferen tiated G3 tumours, probably because FLU acts not only by competing with androgens at receptor level, but also by means of postreceptor or antimitotic mechanisms [11], These findings, however, needed confirmation in a larger group of patients, with a longer follow-up period. In the present investigation, 100 patients with advanced prostatic carcinoma have been studied, 52 of whom were randomized to FLU therapy when relapse occurred dur ing LHRH analogue and CPA treatment. In the remain ing 48 cases, CPA treatment was repeated. The mean duration of follow-up was 39 months in patients treated with CPA and 24 months in patients treated with FLU.
Fig. 1. Plasma concentrations of gonadotropin LH, FSH and of PRL in patients with advanced prostatic cancer during long-term treatment with LHRH analogue combined with CPA or FLU.
Fig. 3. Changes in PAP concentrations in patients with advanced prostatic cancer during long-term treatment with LHRH analogue combined with CPA or FLU.
those found during treatment with LHRH analogue + CPA. A reduction is also observed in plasma A and DHEAS concentrations, but the values are higher than those found during the combination therapy with CPA: 0.80-1.1 and 800-870 ng/ml, respectively, during the whole period of treatment (fig. 2).
Di Silverio/Sciarra/D’Eramo
Fig. 2. Plasma concentrations of T, A and DHEAS in patients with advanced prostatic cancer during long-term treatment with LHRH analogue combined with CPA or FLU.
Clinical Response LHRH Analogue + CPA. The 48 patients with pros tatic carcinoma in relapse, who continued with CPA treatment, all in stage D1-D2 (7 Gl, 12 G2 and 29 G3), showed no objective or subjective improvement, re maining in progress. PAP was increased in all patients with values up to 122 ng/ml and remained elevated between 10 and 17 ng/ml during the second cycle of combination therapy (fig. 3). Twenty-nine patients died within 6 months, 14 within 1 year and the remaining 5 within 18 months from the start of the randomized treatment with CPA. Median survival in this group was 9.3 ± 2 months (fig. 4). LHRH Analogue +FLU. Of the 52 patients in relapse treated with FLU, all in stage D1-D2 (5 Gl, 18 G2 and 29 G3), 45 showed a subjective improvement according to the protocol criteria; in 26 patients with bone métas tasés bone pain showed complete regression in 11 and was substantially reduced in 5 cases, whilst in another 5 stabilization was observed (table 1). Median time to subjective response was 5 months in stage D1 and 1.8 months in stage D2. Regarding, the overall objective response rate in stage D1 prostatic carDownloaded by: University of Exeter 144.173.6.94 - 5/4/2020 7:56:27 AM
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Flutamide in Pretreated Prostatic Cancer
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Table 1. FLU effect on pain in stage D2 prostatic carcinoma Cases Improvement
Stabilization Worsening
from severe to absent from severe to moderate from moderate to absent
3 5 8 5 5
Discussion
cinoma, after 6 months of FLU treatment CR occurred in 4 patients (2 G2 and 2 G3), PR in 11 (2 G2 and 9 G3), SD in 10 (4 Gl, 4 G2 and 2 G3) and PROGR in 1 patient (G3), whereas in the stage D2 group, after 6 months treatment, no CR was observed, only 1 case (G3) being in PR and 16 in SD (1 Gl, 2 G2 and 13 G3). Eight cases remained in PROGR (6 G2 and 2 G3). Median time to objective response was 5 months in stage D1 and 3.6 months in stage D2. The highest response rate was observed at a local level, particularly in the primary prostatic tumour, whilst bone métastasés were the main site of progression. PAP levels, increased in all patients before FLU treatment, fell to mean values of 5 ± 1 ng/ml during FLU treatment and increased again to mean values of 9 ± 1.5 ng/ml when relapse occurred (fig. 3). Two patients died before 6 months, 15 died within 12 months, 12 within 18 months and 7 within 24 months. Median survival was 18 ± 2 months in stage D1 and 12 ± 2 months in stage D2 (fig. 4). The response rate was also positive in cases with G3 prostatic carcino ma: in fact, after 12 months of FLU treatment 1 patient was in CR, 7 were in PR and 10 in SD, and after 18 months 5 were still in PR and 6 in SD.
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Fig. 4. Survival rate in patients with stage D1 and D2 prostatic cancer treated with LHRH analogue combined with CPA or FLU.
Complete androgen inhibition in our patients with advanced prostatic carcinoma was obtained using a com bination therapy with an LHRH analogue and CPA given at the beginning of treatment, in order to eliminate the risk of disease flare-up, which may occur as a conse quence of the initial rise in plasma T. Adrenal androgens are also neutralized, with a reduction of 50% in plasma DHEAS and A, thus enhancing the action of the antian drogen at target tissue level: in fact, the concentrations of DHT in cancer tissue decrease to 1.5 ng/g tissue after castration alone and drop to 0.2 ng/g tissue with FLU [13]. Validity of the combination therapy is also demon strated experimentally by cancer tissue cultures, where very low androgen levels, comparable to those found after orchiectomy alone, stimulate cell growth [14], Moreover, the 20-30% of non-responders to surgical or medical castration alone may decrease to 10% as found by Labrie et al. [15]. Combination therapy with a long-acting LHRH ana logue + CPA used in the present investigation led to a clinical improvement in 70% of the cases with an in creased duration of remission-stabilization periods up to 12-30 months. Relapse of the disease occurs without sig nificant changes in the hormonal pattern, suggesting the development of androgen-insensitive tumour cells or the development of a population of hypersensitive cells growing in a very poor androgen milieu, as hypothesized by Labrie et al. [15]. According to the second hypothesis, substitution of CPA with a more potent pure antiandrogen, such as FLU, might provide additional benefits. It has been shown in fact that FLU is approximately twice as potent as CPA in inhibiting DHT action and 100% more effec tive in inhibiting DNA synthesis induced by testosterone propionate in the ventral prostate of castrated rats [16]. This compound was employed here as second line ther-
Di Silverio/Sciarra/D’Eramo
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present series remission was observed after 6 months FLU therapy in 12 cases with G3 tumour, after 12 months in 9, after 18 months in 5 and after 24 months of FLU therapy in 2, whilst stabilization was found after 6, 12, 18 and 24 months FLU therapy in 15, 10, 6 and 5 cases, respectively. This interesting observation suggests that the effect of FLU in this instance may be non-hormonal, probably exerting an antimitotic action. Further investigations are needed to elucidate the mechanism of action of FLU other than that of receptor blockade. Moreover, it is important to underline that FLU also exerts an analgesic effect: in fact, relief of bone pain, even when the disease is in progress, has been observed in 65% of our patients in stage D2, suggesting that this effect is not mediated by a direct antitumoral action but probably through its phenacetin-like properties. In conclusion, in advanced prostatic carcinoma, CPA may be used as first line therapy in combination with surgical or medical castration, in order to neutralize the effects of adrenal androgens. Relapse, probably condi tioned by the prevalence of an androgen-resistant neo plastic cell population, may still be controlled by FLU, which is also effective in undifferentiated tumours, prob ably acting as an antimitotic drug on prostatic cancer cells, but not on distant métastasés. FLU therapy, how ever, may also be usefully employed in stage D2, since this compound possesses an analgesic effect.
References 1 Di Silverio, F.; Sciarra, F.: Therapeutic approaches in prostatic cancer. J. Steroid Biochem. 25: 773-779 (1986). 2 Nesbit, R.M.; Baum, W.C.: Endocrine control of prostatic carci noma: clinical and statistical survey of 1818 cases. JAMA 143: 1317-1320 (1950). 3 Jordan, W.B.; Blackard, C.E.; Byar, D.P.: Reconsideration of orchiectomy in the treatment of advanced prostatic carcinoma. Sth. med. J. 70: 1411-1413 (1977). 4 Mettelin, C.; Natarajan, N.; Murphy, G.P.: Recent patterns of care of prostatic cancer patients in the United States: results from the surveys of the American College of Surgeons Commis sion on Cancer. Int. Adv. Surg. Oncol. 3: 277-321 (1982). 5 Murphy, G.P.; Beckley, S.; Brady, M.F.; et al.: Treatment of newly diagnosed metastatic prostate cancer patients with che motherapy agents in combination with hormones versus hor mones alone. Cancer 51: 1264-1272 (1983). 6 Di Silverio, F.; Tenaglia, R.; Bigio, A.; et al.: Trattamento del carcinoma prostatico avanzato con un agonista dello LH.RH somministrato da solo o in combinazione con il ciproterone ace tato; in Motta, Serio, Terapia ormonale della patologia prostati ca: aspetti di base e clinici, pp. 74-87 (Medicom Europe, Am sterdam 1988). Downloaded by: University of Exeter 144.173.6.94 - 5/4/2020 7:56:27 AM
apy in 52 patients in relapse after treatment with LHRH analogue + CPA: the remaining 48 patients, also in relapse with the same treatment, but who continued with CPA therapy at the previous dosage, were considered as controls. The two groups were identical as far as mean age, stage distribution and histological grade was concerned. Progress of the disease was confirmed in all the patients who continued with CPA treatment: median survival was 9.3 + 2 months, ranging between 1 and 18 months, regardless of the histological grade. In the FLU-treated group, on the contrary, analysis of the overall objective response showed a significant difference (p < 0.05) in stage D1 when compared to stage D2. In fact, in stage D2 the response was poor and the survival rate (12 ± 2 months) was comparable to that of the CPA group, whilst in stage Dia clinical improvement was observed in approximately 50% of the cases, with a median sur vival of 18 ± 2 months. This clinical response was inde pendent of the hormonal pattern which was character ized by castration levels of plasma T, as seen in the CPA-treated group: moreover, the decrease in plasma concentrations of A and DHEAS was less pronounced in comparison with that observed during the previous treatment. Other investigators have reported a poor response to FLU after a first cycle of conventional hormonal thera py: Sogani et al. [ 17] observed a clinical improvement of short duration in 6 out of 26 patients who had become refractory to previous endocrine therapy, Johansson et al. [ 18] in almost all the patients studied and Stoliar and Albert [ 19] in 7 out of 15 patients. The survival rate was significantly higher when compared to patients treated with orchiectomy alone or estrogens, but no different to that obtained when orchiectomy was associated to estro gens or CPA. The present results in stage D2 patients confirm these findings, which may be partially explained by the fact that FLU exerts a particularly efficacious effect upon the prostatic tumour but not on distant métastasés. This observation is supported by the good results obtained in stage D1 patients with only locally advanced tumour. Furthermore, FLU may reduce the volume of the pri mary tumour also in those cases with distant métastasés in progression. From a theoretical point of view one would expect the best results to be obtained in more differentiated pros tatic carcinoma, such as G1-G2, with adequate andro gen receptor content. However, a good response rate is also reached in undifferentiated tumours: in fact, in the
Flutamide in Pretreated Prostatic Cancer
15 Labrie, F.; Dupont, A.; Cusan, L.; et al.: Combination therapy with flutamide and castration (LH.RH agonist or orchiectomy) in previously untreated patients with clinical stage D2 prostate cancer: today’s therapy of choice. J. Steroid Biochem. 30: 107— 117 (1988). 16 Poyet, P.; Labrie, F.: Comparison of the antiandrogenic-androgenic activities of flutamide, cyproterone acetate and megestrol acetate. Mol. cell. Endocrinol. 42: 283-288 (1985). 17 Sogany, P.C.; Vagaiwala, M.R.; Whitmore, W.F., Jr.: Experience with flutamide in patients with advanced prostatic cancer with out prior endocrine therapy. Cancer 54: 744-750 (1984). 18 Johansson, J.; Andersson, S.; Beckman, K.; et al.: Clinical eval uation of flutamide and estramustine as initial treatment of met astatic carcinoma of prostate. Urology 29: 55-59 (1987). 19 Stoliar, B.; Albert, P.J.: SCH 13521 in the treatment of advanced carcinoma of the prostate. J. Urol. Ill: 803-807 (1974).
Prof. Franco Di Silverio Clinica Urologica Università di Roma ‘La Sapienza’ Policlinico Umberto I Viale del Policlinico 1-00161 Rome (Italy)
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7 Di Silverio, F.; Sciarra, F.: Results of long-term treatment with cyproterone acetate (CPA) in advanced prostatic cancer pa tients; in Klosterhalfen, Endocrine management of prostatic cancer. New developments in biosciences, voi. 4, pp. 115-120 (De Gruyter, Berlin 1988). 8 Geller, J.; Albert, J.; Loza, D.; et al.: DHT concentrations in human prostatic cancer tissue. J. clin. Endocr. Metab. 46: 440453 (1978). 9 Di Silverio, F.; Sciarra, F.; Tenaglia, R.; et al.: Flutamide treat ment of stage D prostatic cancer patients; in Giuliani, Boccardo, Santi, New trends in diagnosis and treatment of prostatic cancer, pp. 167-171 (Acta Medica, Roma 1987). 10 Labrie, F.; Dupont, A.; Belanger, A.; et al.: Combination therapy with flutamide and castration (LH.RH agonist or orchiectomy) in advanced prostate cancer: a marked improvement in response and survival. J. Steroid Biochem. 23: 833-841 (1985). 11 Neri, R.; Kassem, N.: Biological and clinical properties of antiandrogens. Prog. Cancer Res. Ther. 31: 507-518 (1984). 12 Toscano, V.; Petrangeli, E.; Adamo, M.; et al.: Simultaneous determination of 5-alpha reduced metabolites of testosterone in human plasma. J. Steroid Biochem. 6: 575-578 (1981). 13 Labrie, F.; Luthy, L; Veilleux, R.; et al.: New concepts on the androgen sensitivity of prostate cancer; in Murphy, Proc. 2nd Int. Symp. Prostate Cancer, pp. 145-172 (Liss, New York 1987). 14 Labrie, F.; Veilleux, R.: A wide range of sensitivities to andro gens developed in cloned Shionogi mouse mammary tumor cells. Prostate 8: 293-300 (1986).
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