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PubMed2004

Chemohormonal therapy as primary treatment for metastatic prostate cancer: a randomized study of estramustine phosphate plus luteinizing hormone-releasing hormone agonist versus flutamide plus luteinizing hormone-releasing hormone agonist.

BACKGROUND: The present study was undertaken mainly to investigate whether chemohormonal therapy with estramustine phosphate plus luteinizing hormone-releasing hormone (LHRH) agonist has a more beneficial effect than the hormonal therapy with flutamide plus LHRH agonist for newly diagnosed patients with metastatic prostate cancer. METHODS: A total of 57 patients with metastatic prostate cancer aged 59-80 years (median 74 years) were entered in the study and were randomized to the treatment of estramustine phosphate (560 mg/day) plus LHRH agonist (estramustine group) or flutamide (375 mg/day) plus LHRH agonist (flutamide group) with stratification for the degree of performance status, histological differentiation and bone metastasis. RESULTS: Both of the treatment regimens were well tolerated with similar incidences of adverse drug reactions. The overall response rates (complete response plus partial response) at 12 weeks after treatment in the estramustine and flutamide groups were 76 and 55%, respectively. The median time to objective progression for the estramustine group (25.4 months) was longer than that of the flutamide group (14.6 months). The serum levels of follicle stimulating hormone and testosterone were significantly lower in the estramustine group. CONCLUSIONS: Chemohormonal therapy with estramustine phosphate plus LHRH agonist showed longer clinical progression-free survival than the hormonal therapy with flutamide plus LHRH agonist (P = 0.03), although there was no significant difference in the overall survival. A larger-scaled trial with more statistical power is required to clarify that the former regimen is more beneficial than the latter for newly diagnosed patients with advanced prostate cancer.

Aged↗
PubMed2007

Influence for testicular development and histological peculiarity in the testes of flutamide-induced cryptorchid rat model.

OBJECTIVES: To investigate influence for the testicular development and to assess the usefulness as an animal model, cryptorchid rats were induced by exposure to flutamide during the fetal period and their testes examined histologically. METHODS: Flutamide was injected into the abdomen of pregnant rats for 7 days from the 14th to 20th day of gestation. The male offspring in which cryptorchidism was observed at 28 days after birth were defined as the model rats. They were divided into four groups by dosage of flutamide (2.5 mg, 5 mg, 7.5 mg, 15 mg per day), and their testicular weight, spermatogenesis (modified Johnsen score), and germ cell apoptosis were examined histochemically at 10 weeks after birth. RESULTS: The incidence of cryptorchidism including both unilateral and bilateral in the 2.5, 5, 7.5 and 15-mg flutamide groups was 58.3%, 81.9%, 93.6% and 91.0%, respectively. In the model rats, the undescended testes were located at the caudal end of the abdominal cavity, and these testes weighed less than the contra-descended testes in each group. Histologically, apoptotic cells were markedly increased, the seminiferous tubules were degenerated and disturbance of spermatid differentiation was observed in the undescended testes compared with the normal or contra-lateral descended testes. CONCLUSIONS: We found out that the incidence of undescended testes increased in a flutamide dose-dependent manner. The findings of histological examination were independent of the administrated dose of flutamide and it is suggested that exposure of the testes to abdominal temperature causes spermatogenic arrest with germ cell apoptosis. The present animal model indicates high incidence of above 90%, has no surgical stress and dose not require special techniques. We believe that the present model is a useful tool for the understanding of pathogenesis and treatment of cryptorchidism and further biological research into spermatogenesis.

Animals↗
PubMed1999

Frequency of flutamide induced hepatotoxicity in patients with prostate carcinoma.

To identify and describe the frequency and severity of hepatotoxicity in patients who received flutamide therapy for prostate cancer, 22 patients were treated with the combination of flutamide and goserilin or orchiectomy. After diagnosis and staging of prostate cancer, baseline results were obtained for a set of five liver function tests (LF Ts). Hepatotoxicity was assessed according to the WHO criteria. After initiation of flutamide therapy, LF Ts were performed at 4, 8 and 12 weeks and every 2 months thereafter. Severe hepatotoxicity appeared in two of 22 (9%) patients. Following the discontinuation of flutamide, one patient died due to acute liver failure. On the other patient an improvement of LF Ts occurred after cessation of flutamide. The observed severe hepatotoxicity in two of 22 (9%) patients occurred more frequent than is predicted in the literature. Patients treated with flutamide, having symptomatic or asymptomatic liver enzyme elevations, should be taken off therapy as soon as possible.

Aged↗
PubMed2006

Androgen-dependent mechanisms of Wolffian duct development and their perturbation by flutamide.

Androgens play a vital role in Wolffian duct (WD) development, but the mechanisms that underlie this are unknown. The present study used in utero exposure of pregnant rats to the androgen receptor antagonist flutamide (50 or 100 mg/kg) to explore possible mechanisms. Pregnant rats were treated from embryonic d 15.5 (E15.5), and WDs were isolated from fetuses from E17.5-E21.5 and from adults. WD morphology was evaluated, and total length of the duct lumen was determined in fetal samples. Fetal WDs were immunostained for androgen receptor and stromal (inner and outer) and/or epithelial-cell-specific markers and analyzed for cell proliferation and apoptosis. In adulthood, most flutamide-exposed males lacked proximal WD-derived tissues, whereas at E18.5-E19.5, a time when the WD has completely regressed in females, a complete normal WD was present in all flutamide-exposed animals. This suggests that flutamide, at doses of 50 or 100 mg/kg, interferes with WD differentiation, not stabilization. Consistent with this, WD elongation/coiling increased in controls by 204% between E19.5 and E21.5 but increased less significantly (103%) in flutamide-exposed animals. This was associated with reduced cell proliferation, but there was no increase in apoptosis or change in expression of androgen receptor mRNA or protein. Flutamide treatment impaired differentiation of inner stromal cells, shown by decreased expression of smooth muscle actin, before effects were noted in the epithelium, consistent with androgens driving WD development via stromal-epithelial interactions. In conclusion, WD differentiation is far more susceptible to blockade of androgen action than is its initial stabilization, and these effects may be mediated by disruption of stromal-epithelial interactions.

Androgen Antagonists↗
PubMed1992

Comparison of the effects of the 5 alpha-reductase inhibitor finasteride and the antiandrogen flutamide on prostate and genital differentiation: dose-response studies.

Studies were performed to compare the effects of 5 alpha-reductase inhibition and antiandrogen receptor blockade on differentiation of male internal and external genital structures and prostate in the rat. Dose-response studies were performed on male rats treated in utero during the period of sexual differentiation with either the potent 5 alpha-reductase inhibitor finasteride or the antiandrogen flutamide. The treated animals were raised to adulthood and killed, and genital structures were evaluated. Treatment with the 5 alpha-reductase inhibitor finasteride at a dose of 25 mg/kg.day resulted in significant feminization of the external genitalia. There was no further feminization of the genitalia at doses up to 300 mg/kg.day. Wolffian ductal differentiation occurred at all doses evaluated. Seminal vesicle weight, however, significantly decreased at 25 mg/kg.day, but without a further decrease at higher doses of the 5 alpha-reductase inhibitor. Vas deferens and epididymal weights were unchanged at all doses evaluated. There was a significant decrease in prostate size at 25 and 50 mg/kg.day, with no further decrease at higher doses. In flutamide-treated animals, complete feminization of the genitalia occurred at 24 mg/kg.day in all animals. At 18 mg/kg.day, Wolffian ductal differentiation occurred, but seminal vesicle weight was decreased. At dosages of 100, 200, and 300 mg/kg.day flutamide, the vas deferens was absent unilaterally or bilaterally, with small remnants of epididymal head and tail present. At dosages of 24 mg/kg.day and above, the prostate was absent. Studies with the 5 alpha-reductase inhibitor finasteride demonstrate the dependency of prostate and male external genital differentiation on dihydrotestosterone (DHT). However, unlike androgen receptor blockade with flutamide, finasteride did not totally abolish prostate differentiation or completely feminize the external genitalia, despite increasingly higher doses. Since there is no evidence of multiple 5 alpha-reductase isoenzymes to date in the rat, these results suggest that testosterone (T) can compensate for DHT to some degree at the level of the androgen receptor. Wolffian differentiation, however, was not affected by inhibition of DHT, demonstrating its T dependency, but seminal vesicle growth was impaired. Thus, inhibition of 5 alpha-reductase activity limits seminal growth potential in adulthood. Studies with the antiandrogen flutamide show that at doses significantly above that required to completely block prostate differentiation and cause genital feminization, Wolffian ductal differentiation is significantly impaired. Thus, higher doses of flutamide are needed to block the paracrine effect of T on the Wolffian ducts.

5-alpha Reductase Inhibitors↗
PubMed1995

Rapid protection of rat spermatogenic stem cells against procarbazine by treatment with a gonadotropin-releasing hormone antagonist (Nal-Glu) and an antiandrogen (flutamide).

GnRH antagonist (Nal-Glu) treatment combined with the antiandrogen flutamide was used to suppress rat spermatogenesis to achieve protection of spermatogonial stem cells against the anticancer drug procarbazine. Daily injections with Nal-Glu alone suppressed spermatogenesis in a dose-responsive manner. However, it was necessary to combine Nal-Glu (600 micrograms/kg.day) with flutamide at 20 mg/kg.day to decrease testicular weight in 2 weeks to less than 0.6 g, a level previously demonstrated sufficient to protect stem cells in our model system. The Nal-Glu-flutamide pretreatment suppressed serum gonadotropin levels and intratesticular testosterone levels (6% of control) and action, resulting in a reversible decrease in the number of late spermatids to 1% of control levels. When rats were given Nal-Glu-flutamide for 2 weeks before a 250 mg/kg dose of procarbazine, recovery of spermatogenesis, as measured by testis weight, testicular sperm head counts, and repopulation indexes, was significantly better than in control rats (no hormonal pretreatment). The protection achieved with Nal-Glu-flutamide was better than that achieved with 2 weeks of testosterone and estradiol treatment. The present results show that Nal-Glu-flutamide protects spermatogonial stem cells against procarbazine and suggest a method of hormonal pretreatment to achieve rapid and efficient protection of spermatogenesis in humans.

Animals↗
PubMed1998

The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women of reproductive age; it is associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. This study was designed to assess the long term effects of a pure androgen receptor blocker, flutamide, on the lipid profile in women with PCOS and to examine the possible mechanisms by which androgens may exert their influence. Seventeen women with PCOS (10 obese and 7 lean) were studied. All subjects received a 12-week course of oral flutamide (500 mg/day). The baseline and posttreatment evaluations included lipid profile, androgen levels, insulin sensitivity, and serum catecholamine determinations. The primary outcome was the change in the ratio of low density lipoproteins (LDL) to high density lipoproteins (HDL). Treatment with flutamide was associated with a significant decrease in the LDL/HDL ratio by 23% (P = 0.005), in total cholesterol by 18% (P < 0.0001), in LDL by 13% (P = 0.002), and in triglycerides by 23% (P = 0.002). Flutamide treatment was also associated with a trend toward an increase in HDL (by 14%; P = 0.14). The effects on lipid profile were found regardless of obesity and were not associated with a change in weight. Furthermore, actions of flutamide on lipid metabolism were not associated with significant changes in circulating adrenaline or noradrenaline, glucose metabolism, or insulin sensitivity. This report has demonstrated for the first time that treatment with the pure antiandrogen, flutamide, may improve the lipid profile and that this effect may be due to direct inhibition of androgenic actions.

Adult↗
PubMed2001

Lack of methemoglobinemia with flutamide.

OBJECTIVE: To determine whether the nonsteroidal antiandrogenic drug flutamide is a clinically relevant inducer of methemoglobinemia in patients with prostatic cancer. METHODS: Fifty consecutive outpatients with prostatic cancer stage D2 entered the study (age 71.1 +/- 7.3 y). Five patients were lost to follow-up; the remaining 45 patients received the recommended oral dose of flutamide 250 mg three times daily. Total hemoglobin (Hb) and methemoglobin (Met-Hb) concentrations were measured on varying days using an ultraviolet/visible-spectrophotometric method with an intra- and interday variability < 8%. In 12 patients, Met-Hb was analyzed before initiating flutamide therapy and after therapy was begun. RESULTS: On average, 2.6 venous blood samples per patient were analyzed with a mean Met-Hb concentration of 1.9% of total Hb. Mean concentrations of > or = 3% were detected in only six patients (13%). The data from 12 patients evaluated before and after initiating flutamide therapy were without significantly different changes. During the study period, no clinical signs of methemoglobinemia were reported or observed. CONCLUSIONS: This study found no clinically relevant increase of Met-Hb concentrations in elderly patients with prostatic cancer during chronic treatment with flutamide. However, clinicians should be aware of the very rare possibility of flutamide-induced methemoglobinemia.

Aged↗
PubMed2002

Flutamide-induced acute renal failure in a patient with metastatic prostate cancer.

Androgen blockage, with either orchiectomy or luteinizing hormone releasing hormone (LHRH) analogs combined with an antiandrogen drug, is the standard treatment for metastatic prostate cancer. Flutamide is a non-steroidal antiandrogen drug that is frequently used for total androgen blockage. We report on a 54-yr-old man with metastatic prostate cancer who developed nonoliguric acute renal failure (ARF) during treatment with flutamide. Following discontinuation of flutamide therapy, his renal functions returned to normal limits within 4 wk. After a rechallenge with flutamide, serum levels of BUN and creatinine increased again. His renal function recovered completely after the cessation of the drug for the second time. This observation confirm that ARF may be clearly attributed to flutamide therapy. Although very rare, flutamide-induced ARF should be considered.

Acute Kidney Injury↗
PubMed2006

Testosterone antagonist (flutamide) blocks ovulation and preovulatory surges of progesterone, luteinizing hormone and oestradiol in laying hens.

The preovulatory release of luteinizing hormone (LH) in the domestic hen occurs after the initiation of a preovulatory surge of testosterone. The objective of this study was to determine whether this testosterone surge has functional significance in the endocrine control of ovulation. Groups of laying hens (n = 10-22) were treated with the androgen receptor antagonist, flutamide, at 8 h intervals for 24 h at doses of 0, 31.25, 62.5, 125 and 250 mg. All doses reduced egg laying (P < 0.001), with the highest dose being the most effective. In a second study, laying hens (n = 9) were treated with 250 mg flutamide at 8 h intervals for 24 h with a control group being given placebo (n = 10). Blood samples were taken for hormone measurements at 2 h intervals for 18 h starting 4 h before the onset of darkness. The percentage of hens laying per day did not differ between groups before treatment (control, 88% vs flutamide, 86%). Ovulation was blocked in all hens treated with flutamide within 2 days while the control hens continued to lay at the pretreatment rate (80%). Preovulatory surges of plasma testosterone, progesterone, oestradiol and LH were observed in control hens but with the exception of testosterone, flutamide treatment blocked the progesterone, oestradiol and LH surges. LH concentrations declined progressively with time in the flutamide-treated hens. It is concluded that inhibition of testosterone action blocks egg laying and the preovulatory surges of progesterone, luteinizing hormone and oestradiol demonstrating a key role for the preovulatory release of testosterone in the endocrine control of ovulation in the domestic hen.

Androgen Antagonists↗
PubMed1996

Comparison of flutamide and cyproterone acetate in the treatment of hirsutism: a randomized controlled trial.

The objective of this study was to compare the efficacy of flutamide and cyproterone acetate in the treatment of hirsutism. Twenty-two women with idiopathic hirsutism were randomized to receive either flutamide or cyproterone acetate. Each patient underwent a complete gynecological examination as well as an endocrinological profile and hematological, hepatic and renal function analyses. Hirsutism scores were determined using a modified Ferriman-Gallwey scoring system. These tests were then repeated at 3 and 9 months of therapy. Eleven patients received 250 mg of flutamide twice daily and 11 patients received 100 mg of cyproterone acetate on days 5-14 of the menstrual cycle. Ferriman-Gallwey scores were decreased significantly in both groups at the end of 9 months. There was a trend towards a better response with flutamide, that did not achieve significance. Another significant difference was the increased sex hormone-binding globulin in both groups. A statistically significant decrease was also observed for the levels of testosterone on both drugs. No subject withdrew from the study due to a side-effect. The data suggest that both flutamide and cyproterone acetate were similarly effective in treatment of hirsutism, and that the pure antiandrogen flutamide is a safe, well-tolerated and effective alternative in treatment.

Adolescent↗
PubMed2000

[Changes in liver function induced by flutamide in patients with prostate cancer (studies in patients treated with total androgen blockage)].

OBJECTIVES: The incidence of flutamide-induced liver toxicity was studied in 30 consecutive patients with prostate cancer who were treated with total androgen blockage (TAB) therapy (luteinizing hormone releasing hormone [LHRH] analogue and flutamide) in our hospital during the last 3 years and in 20 consecutive patients with prostate cancer who were treated by partial androgen blockage (PAB) therapy (LHRH analogue alone). METHODS: Liver function test, including measurement of serum levels of aspartate aminotransferase (AST) alanine aminotransferase (ALT), total cholesterol, total bilirubin, gamma-glutamyl transpeptidase (gamma-GTP), and cholinesterase were performed at regular interval. RESULTS: The incidence of liver toxicity in patients receiving TAB (10 cases of 25 patients) was significantly higher than in patients receiving PAB (2 of 18 patients). Two patients in whom severe liver toxicity developed after receiving TAB were hospitalized. However, after flutamide was discontinued all patients with liver damage recovered with normalization of AST and ALT levels. Levels of total cholesterol and gamma-GTP did not differ significantly in either patient group. In two patients receiving TAB total bilirubin levels showed slight, transient elevations after maximum elevations of AST and ALT. In 80% of patients receiving TAB serum levels of cholinesterase were significantly higher than those in patients receiving PAB. CONCLUSION: These data suggest that the risk of flutamide-induced liver toxicity is significant in patients receiving TAB. However, this damage can be normalized after flutamide has been discontinued. Serum levels of cholinesterase also increase significantly in patients receiving TAB. This previously unreported phenomenon suggests an unknown effect of flutamide on liver function in patients with prostate cancer.

Aged↗
PubMed1999

[Flutamide-induced late cutaneous pseudoporphyria].

BACKGROUND: Pseudoporphyria is a condition characterized by clinical and histological changes resembling porphyria cutanea tarda, in the absence of any demonstrable abnormality in porphyrin metabolism. Etiologies of pseudoporphyria are hemodialysis for chronic renal failure, chronic UV irradiation, and several drugs, particularly naproxen. We report a case of flutamide induced pseudoporphyria. CASE REPORT: A 75-year-old man had prostatic carcinoma and was treated with flutamide for 1-1/2 years. He presented with a several months history of blisters on the back of the hands and fingers, occurring after sun exposures. The bullae were associated with skin fragility and atrophic scarring. Histopathological examination and direct immunofluorescence showed ultrastructural features close to those described in porphyria cutanea tarda. Quantitative analysis of porphyrins in urine and laboratory blood tests were normal. Flutamide was stopped, leading to healing of the lesions, with no relapse after 11 months. DISCUSSION: Flutamide is an antiandrogen used for the treatment of prostatic carcinoma. Its principal side-effect is represented by liver toxicity. Cutaneous side-effects of flutamide are uncommon; three cases of photo-allergic dermatitis have been described, and we report with our observation, the third case of cutaneous pseudoporphyria induced by flutamide.

Aged↗
PubMed2000

Neoadjuvant hormone therapy and radical radiotherapy for localized prostate cancer: poorer biochemical outcome using flutamide alone.

Since a recent meta-analysis of non-steroidal anti-androgen therapy in metastatic prostate cancer concluded that survival was worse compared with medical or surgical androgen withdrawal, we analyzed our experience with flutamide monotherapy and other forms of neoadjuvant hormone therapy (NHT) prior to radiation therapy in clinically localized prostate cancer. A total of 45 patients received flutamide and 328 patients received other NHT. Flutamide patients had higher PSA levels at diagnosis and shorter duration of treatment, which could bias the results against flutamide monotherapy. Kaplan Meier analysis of PSA -- disease free survival showed significantly poorer outcome with flutamide monotherapy. Multivariate analysis supported this conclusion. Until equivalence to other forms of NHT is shown, we do not recommend flutamide monotherapy prior to radical radiation. A prospective randomized trial would be necessary to confirm this conclusion.

Adenocarcinoma↗
PubMed2001

[Clinical efficacy of treatment with low-dose flutamide in maximum androgen blockade therapy].

To prevent treatment withdrawal due to flutamide-induced liver dysfunction, we performed maximum androgen blockade (MAB) therapy by combining a luteinizing hormone-releasing hormone agonist or orchiectomy with low-dose flutamide (125 mg x 2/day) in patients with prostate cancer. In this study, the efficacy, adverse effects such as hepatotoxicity, and compliance were compared retrospectively between 35 patients who received low-dose flutamide therapy (1995-1999) and 27 patients who received flutamide at its ordinary dose (125 mg x 3/day). No significant difference was observed in the response rate (> or = PR) as determined from the prostate-specific antigen parameter (p = 0.6211) or the incidence of hepatotoxicity based on the aspartate aminotransferase and alanine aminotransferase levels. However, flutamide withdrawal due to liver dysfunction was less frequent in the low-dose group (2.9%) than in the ordinary dose group (18.5%) (p = 0.0386). MAB therapy using low-dose flutamide is expected to prevent the reduction in the compliance due to side effects and to improve the long-term prognosis in patients with prostate cancer, who are mostly elderly individuals.

Aged↗
PubMed2001

Flutamide-induced hepatotoxicity: report of a case series.

OBJECTIVE: To evaluate the characteristics of flutamide induced hepatotoxicity. MATERIAL AND METHODS: In this retrospective study we have analyzed all cases of flutamide hepatotoxicity submitted to the Andalucian Registry of drug-induced liver disease. Data were collected using a structured reporting form. Causality assessment was performed using two clinical scales: the standard CIOMS scale and the recently developed María and Victorino scale. RESULTS: Nine of 185 patients (4.9%) were identified. In 8 male patients, mean age 75 years (range 65-83), flutamide was indicated for palliative therapy of disseminated prostatic carcinoma, and in one young female (14 years) was given for the treatment of facial hirsutism. The mean duration of the flutamide therapy was 151 days (range 4-443). All patients presented with overt liver injury, the most frequent features being asthenia, anorexia, weight loss, nausea, vomiting and jaundice. No patient showed hypersensitivity features. In two patients (22%) the hepatic damage evolved to fulminant liver failure, one of them undergoing a liver transplantation and the other subsequently died. An additional patient died of a non-hepatic related cause when his liver function was improving. Causality assessment by the two clinical scales did not exclude any case, but the two patients who died where classified as unlikely by the María and Victorino scale. CONCLUSIONS: Flutamide can induce severe acute hepatitis, probably due to an idiosyncratic metabolic mechanism. Liver tests monitoring should probably be mandatory during the first months of flutamide therapy and the drug withdrawn if transaminases began to increase.

Adolescent↗
PubMed2006

[Impact of flutamide on sex differentiation in rats].

OBJECTIVE: To investigate the adverse effect of flutamide on the sex differentiation of F1 generation male rats and to establish a rat model of hypospadis. METHODS: Sixty pregnant SD rats were divided randomly into one control group and five treatment groups. Flutamide was injected subcutaneously (sc) with normal salin (NS) at a dose of 0, 4882.8, 5078.1, 5273.4, 5468.7, and 6250.0 microg/kg x d to the rats in the above groups respectively during the period of gestation day (GD) 12 to 17. The fetuses of two rats from each group were anatomized on GD18 to extract genital tubercle (GT) to make pathological sections. Meanwhile, the position of testes and the development of prostates were examined. The position of urethral opening and testes were examined on GD2, 13 and 28. RESULTS: The incidence of hypospadias increased with the dose of flutamide (0, 29.00%, 40.00%, 63.68%, 78.72%, and 100% for the above groups respectively). The incidence of single cryptorchidism also increased with the dose of flutamide (0, 4.23%, 6.23%, 9.23%, 11.52%, and 16.28% for the above groups respectively). Flutamide led to 100% incidence of prostate agenesis,100% incidence of female-like areola of nipple, and 100% incidence of female-like anogenital distance (AGD). CONCLUSION: Flutamide can cause abnormal sex differentiation and sex development and induce the experimental model of hypospaias in rats.

Androgen Antagonists↗
PubMed1997

Prostate specific antigen decreases after withdrawal of antiandrogen therapy with bicalutamide or flutamide in patients receiving combined androgen blockade.

PURPOSE: We determined whether decreases in prostate specific antigen (PSA) would occur after withdrawal of double-blinded antiandrogen therapy with flutamide or bicalutamide for clinical progression or increasing PSA concentration in patients receiving combined androgen blockade for advanced prostate cancer. MATERIALS AND METHODS: PSA concentrations were determined weekly for at least 6 weeks and then every other week for 6 weeks in 22 patients with stage D2 prostate cancer. All patients were withdrawn from antiandrogen therapy (8 flutamide and 14 bicalutamide) due to progression or an increasing PSA concentration. Objective response was evaluated before antiandrogen withdrawal and at week 12. RESULTS: In 4 of 8 patients (50%) withdrawn from flutamide and 4 of 14 (29%) withdrawn from bicalutamide serum PSA concentrations decreased by 50% or more. PSA responses after withdrawal of flutamide therapy occurred within the first few days, whereas those after withdrawal of bicalutamide therapy occurred within 4 to 8 weeks. Of 4 patients assessed for objective response 2 had stable disease and 2 had progression. A PSA response was observed in the 2 patients with stable disease but not the 2 with progression. CONCLUSIONS: For patients with stage D2 prostate cancer and disease progression or an increasing PSA concentration, withdrawal of antiandrogen therapy with bicalutamide or flutamide may result in a PSA response. The time to PSA response is longer with bicalutamide than with flutamide. The clinical significance of the antiandrogen withdrawal phenomenon is unknown.

Aged↗