Bicalutamide Therapy Research Articles

Estrogen receptor-α and sex steroid hormones regulate Toll-like receptor-9 expression and invasive function in human breast cancer cells

Toll-like receptor 9 (TLR9) is a cellular DNA-receptor, which is widely expressed in cancer. Synthetic TLR9-ligands induce cancer cell invasion in vitro, but the role of TLR9 in cancer pathophysiology remains unclear. Increased TLR9 expression has been, however, detected in estrogen receptor negative (ER-) breast cancers. In this study, we investigated the effects of ERα expression and sex steroid hormones on TLR9 expression in human ER+ (MCF-7, T47-D) and ER- (MDA-MB-231) breast cancer cell lines in vitro. We also studied TLR9 mRNA expression in archival breast cancer specimens (n = 12) with qRT-PCR, using primer sets that detect only the TLR9A isoform or the isoforms A and B (TLR9A/B). The TLR9 mRNA expression was detected in 10/12 specimens with both primer sets, and in 1/12 with only the TLR9A or the TLR9A/B primer sets. The basal TLR9 mRNA expression levels were significantly lower in the ER+ cell lines as compared with the ER- MDA-MB-231 cells. The transfection of ERα cDNA into MDA-MB-231 cells also resulted in down-regulation of TLR9 expression. While sex steroids had no effect on TLR9 expression in MCF-7 cells, testosterone (10(-8) M) induced TLR9 expression in MDA-MB-231 and T47-D cells. Although bicalutamide blocked this testosterone effect in MDA-MB-231 cells, in T47-D cells bicalutamide increased TLR9 expression and only partially blocked the testosterone effects. Estradiol (10(-8) M) induced TLR9 expression in T47-D cells. The invasive effects of synthetic TLR9-ligands were augmented by testosterone in vitro. This effect was lost in TLR9 siRNA MDA-MB-231 cells and also decreased by over-expression of ERα, which also inhibited NF-κB activation by TLR9-ligands. In conclusion, expression of TLR9 isoforms A and B can be detected in clinical breast cancer specimens. The ERα and sex steroid hormones regulate TLR9 expression and invasive effects in the breast cancer cells. Also, the commonly used hormonal cancer therapy bicalutamide affects TLR9 expression.

The Protective Role Of Ascorbic Acid Administration On The Bicalutamide Induced Reduction In Semen Quality In The Sprague - Dawley Rat.

Antineoplastic drugs used in the treatment of testicular carcinoma have been reported to have deleterious effects on the fertility potentials in affected males. The mechanism of damage involves the generation of free radicals.We evaluated the effect of using an antioxidant ascorbic acid as an adjuvant treatment with Bicalutamide on the androgen sensitive organs of the male Sprague-Dawley rats.Thirty-five adult male Sprague-Dawley rats weighing between 160-180 g were used for the experiment. The animals were randomly selected and divided into seven groups of five rats each. They were given 10 mg/kg or 20 mg/kg body weight of Bicalutamide and 200 mg/kg of Ascorbic acid for three and eight weeks. The animals were sacrificed and the cauda epididymides excised for sperm count and sperm motility analysis.There was observed decrease in semen quality with Bicalutamide that was attenuated by ascorbic acid co-administration. The concomitant administration of ascorbic acid has a protective role on reproductive function in males on Bicalutamide therapy.

Pathological Effects of Prostate Cancer Correlate With Neuroendocrine Differentiation and PTEN Expression After Bicalutamide Monotherapy

Androgen deprivation therapy is the primary treatment for advanced prostate cancer but many patients eventually experience progression to hormone refractory status. Understanding the molecular changes after androgen deprivation therapy would help evaluate the efficacy or failure of second line therapies. Therefore, we analyzed the expression of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), the human epidermal receptor-2 and neuroendocrine differentiation after bicalutamide monotherapy, which is emerging as an alternative treatment for locally advanced prostate cancer. Molecular arrangements were evaluated in 107 radical prostatectomy specimens from patients given 150 mg bicalutamide before surgery. Pathological regressive changes, and the correlation of postoperative biochemical failure with the extent of molecular arrangements and pathological effects were analyzed. Patients with minimal regression effects after bicalutamide therapy had advanced pathological stage disease, and tended to have positive chromogranin A expression and PTEN inactivation. Only 4 (3.7%) prostatectomy specimens showed human epidermal receptor-2 immunostaining. The probability of positive chromogranin A expression in the PTEN inactivation group was 2.5-fold (OR 2.5, 95% CI 1.1-5.6, p = 0.023) higher than in the nonPTEN inactivation group. Cox regression analysis revealed that seminal vesicle invasion, PTEN/chromogranin A expression and lymph node invasion were significant variables for time to biochemical recurrence. PTEN inactivation and neuroendocrine differentiation were related to refractoriness to bicalutamide therapy. These results support the hypothesis that neuroendocrine differentiation is caused by activation of the serine threonine kinase Akt pathway, which results from PTEN inactivation.

Bicalutamide‐Associated Fulminant Hepatotoxicity

Abstract Bicalutamide is a nonsteroidal antiandrogen used extensively during the start of androgen deprivation therapy with a luteinizing hormone-releasing hormone agonist to reduce occurrence of the symptoms of tumor flare in patients with metastatic prostate carcinoma. The most common adverse effects of bicalutamide are induced by its pharmacologic property of competitive androgen receptor blockade and include gynecomastia, hot flashes, fatigue, and decreased libido. Although not as common, increases in liver function test results are also seen with bicalutamide therapy. These elevations are typically transient, and patients remain asymptomatic. We describe a 59-year-old man with metastatic prostate carcinoma treated with bicalutamide as part of androgen deprivation therapy before starting chemotherapy. At baseline, his liver function test results and serum creatinine concentration were within normal limits, and an abdominal computed tomographic scan did not demonstrate liver metastasis. After 4 days of bicalutamide therapy, the patient came to the emergency department with complaints of abdominal pain, distension, and tenderness. His liver function tests were abnormal, and bicalutamide was discontinued. After 2 days of increasing liver function tests and symptoms of hepatotoxicity, the patient developed tachycardia and hypotension that was resistant to fluid resuscitation. Multiorgan damage was manifested by an alanine aminotransferase level greater than 40 times the upper limit of normal, serum creatinine concentration of 4.2 mg/dl, and troponin I level of 18 ng/ml. The patient died 8 days after bicalutamide therapy was begun secondary to multiorgan failure, most likely as a result of fulminant hepatotoxicity. The Naranjo adverse drug reaction probability scale showed a probable (score of 5) causal relationship between bicalutamide and fulminant hepatotoxicity. Fulminant hepatotoxicity is a rare but potentially fatal adverse effect of bicalutamide. Liver function tests should be monitored before and during bicalutamide therapy, even for patients who have previously completed a course of this therapy with no signs or symptoms of toxicity.

11C]Choline uptake with PET/CT for the initial diagnosis of prostate cancer: relation to PSA levels, tumour stage and anti-androgenic therapy

The accuracy of positron emission tomography (PET)/CT with [(11)C]choline for the detection of prostate cancer is not well established. We assessed the dependence of [(11)C]choline maximum standardized uptake values (SUV(max)) in the prostate gland on cell malignancy, prostate-specific antigen (PSA) levels, Gleason score, tumour stage and anti-androgenic hormonal therapy. In this prospective study, PET/CT with [(11)C]choline was performed in 19 prostate cancer patients who subsequently underwent prostatectomy with histologic sextant analysis (group A) and in six prostate cancer patients before and after anti-androgenic hormonal therapy (bicalutamide 150 mg/day; median treatment of 4 months; group B). In group A, based on a sextant analysis with a [(11)C]choline SUV(max) cutoff of 2.5 (as derived from a receiver-operating characteristic analysis), PET/CT showed sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 72, 43, 64, 51 and 60%, respectively. In the patient-by-patient analysis, no significant correlation was detected between SUV(max) and PSA levels, Gleason score or pathological stage. On the contrary, a significant (P < 0.05) negative correlation was detected between SUV(max) and anti-androgenic therapy both in univariate (r (2) = 0.24) and multivariate (r (2) = 0.48) analyses. Prostate [(11)C]choline uptake after bicalutamide therapy significantly (P < 0.05) decreased compared to baseline (6.4 +/- 4.6 and 11.8 +/- 5.3, respectively; group B). PET/CT with [(11)C]choline is not suitable for the initial diagnosis and local staging of prostate cancer. PET/CT with [(11)C]choline could be used to monitor the response to anti-androgenic therapy.

The addition of bicalutamide 150 mg to radiotherapy significantly improves overall survival in men with locally advanced prostate cancer

Castration therapy adjuvant to radiotherapy can significantly improve overall survival compared with radiotherapy alone in patients with locally advanced prostate cancer. Although many of the adverse effects of castration therapy are manageable, they can have a detrimental effect on quality of life. Here we evaluate the efficacy and tolerability of the non-castration-based therapy bicalutamide ('Casodex') 150 mg adjuvant to radiotherapy in patients with T1-4, M0, any n prostate cancer. The subset of patients within the early prostate cancer (EPC) program who received radiotherapy with curative intent (n = 1,370) were included in the analysis. These patients were randomized to receive oral bicalutamide 150 mg once daily (n = 699) or placebo (n = 671). The median follow-up for patients included in this analysis was 7.2 years. In patients with locally advanced disease (n = 305), bicalutamide adjuvant to radiotherapy significantly improved: progression-free survival (PFS), reducing the risk of objective progression by 44% compared with radiotherapy alone [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.40, 0.78; P < 0.001). Prostate-specific antigen (PSA)-PFS, reducing the risk of PSA progression by 59% compared with radiotherapy alone (HR 0.41; 95% CI 0.30, 0.55; P < 0.001). Overall survival, reducing the risk of death by 35% compared with radiotherapy alone (HR 0.65; 95% CI 0.44, 0.95; P = 0.03). This significant overall survival benefit for bicalutamide was driven by a lower risk of prostate cancer-related deaths (16.1 vs 24.3%, respectively). There was no significant difference in PFS or overall survival in patients with localized disease (n = 1,065). In patients with locally advanced disease, bicalutamide 150 mg adjuvant to radiotherapy demonstrates significant clinical benefits in terms of overall survival, PFS and PSA-PFS compared with radiotherapy alone. The overall survival benefit in these patients is consistent with prior studies evaluating castration-based therapies adjuvant to radiotherapy (Bolla et al. in Lancet 360:103-108, 2002; Pilepich et al. in Int J Radiat Oncol Biol Phys 61:1285-1290, 2005). In addition, the clinical benefit of bicalutamide 150 mg in locally advanced patients, but not in those with localized disease, is consistent with the overall results from the EPC program (McLeod et al. BJU Int 97:247-254, 2006). Given the quality-of-life advantages of bicalutamide relative to castration, bicalutamide 150 mg adjuvant to radiotherapy is an attractive alternative for men with locally advanced prostate cancer.

Reducing the gynecomastia and breast pain associated with bicalutamide therapy

Reducing the gynecomastia and breast pain associated with bicalutamide therapy

Reducing the gynecomastia and breast pain associated with bicalutamide therapy

Reducing the gynecomastia and breast pain associated with bicalutamide therapy

GYNECOMASTIA AND BREAST PAIN INDUCED BY ADJUVANT THERAPY WITH BICALUTAMIDE AFTER RADICAL PROSTATECTOMY IN PATIENTS WITH PROSTATE CANCER: THE ROLE OF TAMOXIFEN AND RADIOTHERAPY

We investigated the role of tamoxifen and radiotherapy (RT) for the prevention and treatment of gynecomastia and breast pain during adjuvant bicalutamide monotherapy after radical prostatectomy (RP) in patients with prostate cancer. Also, we evaluated their effects on patient hormonal status, quality of life (QOL), sexual function and prostate specific antigen relapse-free survival. This was a multicenter prospective trial. From January 2002 to February 2004, 102 patients who had undergone RP for localized or locally advanced prostate cancer were recruited and randomized into 3 groups, namely group 1-those receiving only 150 mg bicalutamide as adjuvant hormonal therapy, group 2-those receiving bicalutamide and 10 mg tamoxifen, and group 3-those receiving bicalutamide and RT. Patients in group 1 in whom gynecomastia or breast pain developed were subsequently randomized to receive tamoxifen or RT soon after symptoms started. Gynecomastia, breast pain, prostate specific antigen, QOL, sexual function and hormonal levels were assessed. Minimum followup was 12 months. Of group 1 patients 67% had gynecomastia compared with 8% in group 2 and 34% in group 3. Breast pain was more frequent in group 1 than in groups 2 and 3 (58% vs 7% and 30%, respectively). Differences were significant between groups 1 and 2 (OR 0.12 p <0.001), and groups 1 and 3 (OR 0.52 p < 0.01). In patients in group 1 who had gynecomastia or breast pain a significant decrease in symptoms was achieved in those receiving tamoxifen (p <0.05). Treatments were well tolerated in the 3 groups. No differences in QOL between groups 2 and 3 were found. At a median followup of 26 months we observed 12 biochemical relapses. Gynecomastia and breast pain induced by bicalutamide monotherapy after RP can be prevented and treated. Tamoxifen has been shown to be more effective and safe than RT in this setting. QOL and sexual function are not negatively influenced by these 2 treatment options.

A phase II study of nilutamide in men with prostate cancer after the failure of flutamide or bicalutamide therapy

To determine the prostate-specific antigen (PSA) response and time to PSA or radiographic progression in men with prostate cancer refractory to bicalutamide and/or flutamide therapy. Men with histologically confirmed prostate cancer not amenable to curative surgery or radiation therapy were eligible for the study if they had radiographic or PSA progression on at least one antiandrogen (not nilutamide) despite continued androgen suppression and standard antiandrogen withdrawal periods. All men received nilutamide 150 mg/day orally for > or = 8 weeks unless there was unacceptable toxicity or disease progression. All men were evaluated for response, safety and toxicity. Baseline PSA levels, chest X-ray, bone scan and abdominopelvic computed tomography studies were obtained; the re-evaluation included PSA levels every 4 weeks and repeated imaging every 8 weeks in those with baseline abnormalities. The chest X-ray was repeated if there were pulmonary symptoms. Nineteen men were consented and 16 were evaluable for response. The median (range) Gleason score was 7 (6-9) and the median number of previous second-line therapies was 2 (1-4). Bicalutamide therapy had failed in all patients. At baseline, 13 (of 16 men) had radiographically evident disease, nine with diffuse osseous and four with radiographically measurable metastases. There was no grade 3/4 toxicity; the commonest grade 1/2 toxicities were constipation (three), sensory neuropathy (four), fatigue (six), and visual changes (two) involving transiently altered colour vision and sensitivity to light, respectively. Responses included three partial and 13 with progressive disease. The study was discontinued after a planned interim analysis because nilutamide had no apparent activity. Although well tolerated, nilutamide offers benefit to few men with prostate cancer in whom bicalutamide has failed.

Prolonged Response to Nilutamide in a Patient with Stage D0.5 Prostate Cancer Who Previously Failed Androgen Deprivation Therapy

There is currently no standard therapy for patients with prostate cancer who have progressive rise in PSA levels despite treatment with hormonal ablation and antiandrogen withdrawal (stage D0.5). One potential treatment option is the use of a different androgen receptor antagonist (ARA), such as nilutamide. We report a case of a 66-year-old gentleman with greater than a 46 month sustained response to nilutamide therapy after failing bicalutamide therapy and its subsequent withdrawal. The patient continues to have undetectable PSA levels and an excellent performance status. This case demonstrates the prolonged response to a second-line ARA in patients deemed to have androgen insensitive prostate cancer. Further investigation of the potential role of nilutamide therapy as second-line antiandrogen therapy is warranted as monotherapy and/or in combination with other promising novel approaches including PSA-based vaccines.

Tamoxifen may reduce symptoms of bicalutamide therapy

Tamoxifen may reduce symptoms of bicalutamide therapy

A phase II study of nilutamide in men with prostate cancer following failure of flutamide or bicalutamide therapy

4669 Background: Determine PSA response, time to PSA progression and, in a subset with measurable disease at baseline, the objective response rate and time to radiographic progression in men with prostate cancer refractory to bicalutamide and/or flutamide therapy. Methods: Eligibility included histologically confirmed prostate cancer not amenable to curative therapy with either radiation or surgery and progressive disease demonstrated by radiographic or PSA criteria. Patients progressing on bicalutamide therapy must have undergone a 6-week anti-androgen withdrawal period while those progressing on flutamide were eligible following a 4-week withdrawal. All subjects received nilutamide, 150 mg/day orally, for a minimum of 8 weeks; patients were evaluable for PSA and radiographic response after 4 and 8 weeks, respectively. A baseline PSA, CXR, bone scan and abdominal/pelvic CT were obtained; re-evaluation included PSA every 4 weeks and repeat radiographic imaging for those with baselines abnormalities. A 50% PSA decline without radiographic progression was considered a partial response. CXR was repeated for any pulmonary symptoms. Results: To date, 13 men have been enrolled and 11 are evaluable. Median Gleason's score at diagnosis was 7 (range 6–9). Median number of prior therapies was 3 (range 1–5). Median baseline PSA was 16.7 ng/ml (range 4.9–151 ng/ml). 8 subjects had diffuse bone metastases and 3 had other radiographically measurable disease. Of these, 2 are not yet radiographically evaluable (on study < 8 weeks) and one has radiographic stable disease at 8 weeks. There have been no grade 3/4 toxicities; the most common grade 1/2 toxicities were constipation (2), sensory neuropathy (3), fatigue (3), and visual changes (2) involving transient change in color vision and sensitivity to light, respectively. Responses include 2 (18%) PR and 5 (45%) PD. Those progressing did so after 8 weeks of therapy and by PSA criteria only. Conclusions: Nilutamide is well tolerated and leads to PSA responses following bicalutamide or flutamide failure. Ongoing study will determine the response rate and duration of response for this third line hormonal approach. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis

A phase II study of nilutamide in men with prostate cancer following failure of flutamide or bicalutamide therapy

4669 Background: Determine PSA response, time to PSA progression and, in a subset with measurable disease at baseline, the objective response rate and time to radiographic progression in men with prostate cancer refractory to bicalutamide and/or flutamide therapy. Methods: Eligibility included histologically confirmed prostate cancer not amenable to curative therapy with either radiation or surgery and progressive disease demonstrated by radiographic or PSA criteria. Patients progressing on bicalutamide therapy must have undergone a 6-week anti-androgen withdrawal period while those progressing on flutamide were eligible following a 4-week withdrawal. All subjects received nilutamide, 150 mg/day orally, for a minimum of 8 weeks; patients were evaluable for PSA and radiographic response after 4 and 8 weeks, respectively. A baseline PSA, CXR, bone scan and abdominal/pelvic CT were obtained; re-evaluation included PSA every 4 weeks and repeat radiographic imaging for those with baselines abnormalities. A 50% PSA decline without radiographic progression was considered a partial response. CXR was repeated for any pulmonary symptoms. Results: To date, 13 men have been enrolled and 11 are evaluable. Median Gleason's score at diagnosis was 7 (range 6–9). Median number of prior therapies was 3 (range 1–5). Median baseline PSA was 16.7 ng/ml (range 4.9–151 ng/ml). 8 subjects had diffuse bone metastases and 3 had other radiographically measurable disease. Of these, 2 are not yet radiographically evaluable (on study < 8 weeks) and one has radiographic stable disease at 8 weeks. There have been no grade 3/4 toxicities; the most common grade 1/2 toxicities were constipation (2), sensory neuropathy (3), fatigue (3), and visual changes (2) involving transient change in color vision and sensitivity to light, respectively. Responses include 2 (18%) PR and 5 (45%) PD. Those progressing did so after 8 weeks of therapy and by PSA criteria only. Conclusions: Nilutamide is well tolerated and leads to PSA responses following bicalutamide or flutamide failure. Ongoing study will determine the response rate and duration of response for this third line hormonal approach. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis

1069: Once Weekly Tamoxifen in the Prevention of Gynaaecomastia and Breast Pain Secondary to Bicalutamide Therapy

1069: Once Weekly Tamoxifen in the Prevention of Gynaaecomastia and Breast Pain Secondary to Bicalutamide Therapy

Adjuvant hormone therapy after radiation or surgery for localized or locally advanced prostate cancer.

Prostate cancer is being diagnosed at an earlier age and earlier disease stage than previously and increasing numbers of relatively young men are receiving potentially curative radical prostatectomy or radiotherapy for early prostate cancer. Although many of these men have an excellent outcome, a significant proportion subsequently experience disease recurrence or cancer-related death. Men with unfavorable tumor characteristics at the time of radical prostatectomy or radiotherapy are particularly at high risk of experiencing disease recurrence. One strategy to improve outcome for these men is adjuvant hormone therapy (hormone therapy administered immediately after therapy of primary curative intent). Surgical castration (bilateral orchiectomy), medical castration using the luteinizing hormone-releasing hormone (LHRH) agonist goserelin, and antiandrogen monotherapy have been investigated as adjuvant hormone therapy to radical prostatectomy and radiotherapy, and each therapy has demonstrated clinical benefits because of a significant improvement in disease-free survival. Furthermore, data are available to indicate that adjuvant hormone therapy achieved by goserelin or bilateral orchiectomy improves overall survival, particularly in men at high risk of progression. Because the effects of LHRH agonists are reversible, they provide a more acceptable method of adjuvant therapy compared to bilateral orchiectomy, particularly in the adjuvant setting, and are preferred by patients. However, the adverse effects on quality of life, in particular on sexual interest and function and bone mineral density, may limit the use of LHRH agonists in some patients. However, these parameters are maintained with nonsteroidal antiandrogens. The first data from the Early Prostate Cancer program indicate that adjuvant bicalutamide 150 mg is associated with a significant improvement in progression-free survival after radical prostatectomy or radiotherapy. Gynecomastia and breast pain are the most common side effects associated with bicalutamide therapy. Medical or surgical castration in combination with an antiandrogen (combined androgen blockade) is another option for use as an adjuvant hormone therapy. However, no study has reported on the use of combined androgen blockade in this setting. Adjuvant hormone therapy provides clinicians with another treatment option for patients with early prostate cancer and unfavorable tumor characteristics.

Emerging role of adjuvant hormonal therapy

Recent years have seen a downward shift in the most common disease stage at diagnosis and in the age of patients diagnosed with prostate cancer. Although younger men with clinically localized disease are generally offered radiotherapy or radical prostatectomy, such treatment does not always produce a cure. Adjuvant hormonal therapy (medical or surgical castration) has been shown to extend progression-free survival in both the radiotherapy and surgical settings, and overall survival benefits have also been demonstrated in some studies. However, castration is associated with sexual dysfunction that may be unacceptable, particularly among younger patients. The ongoing bicalutamide (Casodex; AstraZeneca Pharmaceuticals, Wilmington, DE) Early Prostate Cancer program is evaluating the efficacy and tolerability of bicalutamide 150 mg as immediate therapy, either alone or as an adjuvant to therapy of curative intent, in patients with localized or locally advanced prostate cancer. This is the largest clinical trial program in prostate cancer treatment to date, comprising 3 randomized, double-blind, placebo-controlled studies with a total of 8113 patients. At median follow-up period of 3 years and after 922 progression events, the bicalutamide group had a significant reduction of 42% in the risk of objective progression compared with patients who received placebo plus standard care. The risk of prostate-specific antigen progression was also significantly reduced by 59%. As expected, gynecomastia and breast pain were the most frequently reported side effects of bicalutamide therapy. A longer follow-up period will determine whether the reduced risk of progression will translate into cause-specific and overall survival benefit for these patients.

Lack of Effect of Aminoglutethimide and Hydrocortisone Added to High‐Dose Bicalutamide for Androgen‐Independent Prostate Cancer

ABSTRACTObjectives: To determine whether hormones derived from the adrenal gland affected the progression of androgen‐independent (AI) prostate cancer for patients already receiving treatment with high‐dose bicalutamide. This was accomplished by using a sequential trial design in which medically or surgically castrated patients with AI prostate cancer whose cancers were progressing while receiving bicalutamide were treated with adrenolytic therapy in the form of aminoglutethimide (AM) and hydrocortisone (HC).Materials and Methods: Sixteen patients with AI prostate cancer were enrolled into this trial. All patients had metastatic disease in the bone, and two patients had additional metastases at other sites. Using prostate specific antigen (PSA) level as an indicator of disease activity, patients initially received bicalutamide therapy, then AM and HC were added to the regimen, and then bicalutamide therapy was discontinued, with each documented PSA level increase (see Figure 1). Clinical Trial Study Design: Patients were treated with sequential hormonal interventions according to the scheme depicted above. imageResults: Four (25%) patients demonstrated PSA level reductions of at least 50% after the initiation of bicalutamide, 150 mg/day. No patient demonstrated a PSA or obvious clinical response to the addition of AM and HC to the regimen. This includes the four patients who were initially sensitive to bicalutamide. Therapy with AM and HC was associated with fatigue and skin rashes. These side effects persisted after the withdrawal of bicalutamide therapy and were therefore attributed to AM and HC therapy.Conclusions: Bicalutamide at high doses seems to effectively block the androgen receptor (AR) from the growth stimulation derived from adrenal hormones. Therefore, the inhibition of adrenal hormone production by AM is not a useful therapeutic maneuver in this setting and is associated with moderate side effects. The activation of the AR pathway in these patients may occur by a mechanism other than stimulation by the androgens derived from the testes or adrenal gland.

Comparison of goserelin and leuprolide in combined androgen blockade therapy

Objectives. To perform exploratory analyses of data from a controlled trial that assessed the efficacy and tolerability of two antiandrogens, bicalutamide and flutamide, each combined with monthly depot preparations of leuprolide or goserelin, in patients with Stage D2 prostate cancer. One analysis compared goserelin plus antiandrogen therapy with leuprolide plus antiandrogen therapy; a second analysis compared the four combined androgen blockade (CAB) regimens. Methods. This was a randomized, multicenter trial, open-label for luteinizing hormone releasing hormone analogue (LHRH-A) therapy, double-blind for antiandrogen therapy, with a two-by-two factorial design. Eight-hundred thirteen patients were allocated in a ratio of 2:1 to goserelin therapy (3.6 mg every 28 days) or leuprolide therapy (7.5 mg every 28 days) and 1:1 to bicalutamide therapy (50 mg once a day) or flutamide therapy (250 mg three times a day). The end points of time to progression and survival were assessed with a median of 160 weeks of follow-up. Results. The percentages of progression events (70.9% versus 73.3%) and deaths (54.3% versus 56.8%) were similar for goserelin plus antiandrogen and leuprolide plus antiandrogen therapies. The hazard ratios for goserelin plus antiandrogen therapy to leuprolide plus antiandrogen therapy were 0.99 (95% confidence interval [CI] 0.84 to 1.18; P = 0.92) and 0.91 (95% CI 0.75 to 1.11; P = 0.34) for time to progression and survival, respectively. Goserelin plus antiandrogen and leuprolide plus antiandrogen therapies were generally well tolerated, and the side effects associated with depot administration occurred with a low frequency in the two groups. There were no significant differences among the goserelin plus bicalutamide, goserelin plus flutamide, or leuprolide plus bicalutamide therapy groups, but leuprolide plus flutamide therapy had a significantly poorer outcome than the other three therapies. The side-effect profiles for the four CAB groups were generally similar; diarrhea was more common among patients treated with flutamide and hematuria was more common among patients treated with bicalutamide. Conclusions. Although the results of these exploratory analyses should be interpreted with caution, they indicate that goserelin plus antiandrogen and leuprolide plus antiandrogen therapies are similarly well tolerated and have equivalent time to progression and survival, and that leuprolide plus flutamide therapy appears to be the least effective of the four CAB regimens.

Casodex (bicalutamide) 150-mg monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer: results from two multicenter randomized trials at a median follow-up of 4 years

Objectives. To compare the efficacy, tolerability, and quality of life benefits of bicalutamide (Casodex) 150-mg/day monotherapy and castration in previously untreated nonmetastatic (MO) advanced prostate cancer. Methods. A total of 480 patients with Stage T3/T4 nonmetastatic disease randomly received oral bicalutamide 150 mg/day or castration (either bilateral orchiectomy or goserelin acetate [Zoladex] 3.6 mg every 28 days) in a 2:1 ratio in two open multicenter studies (studies 306 and 307). The design of these studies was similar to allow a pooled analysis. Results. In the combined survival analysis, at median follow-up of 202 and 205 weeks in studies 306 and 307, respectively, with 31% of the cases resulting in death, bicalutamide 150-mg monotherapy was statistically equivalent to castration; the risk of death from any cause was 7% less with bicalutamide than with castration (hazard ratio [HR] = 0.93). Data on time to treatment failure and objective progression could not be pooled, as results for these end points differed between the trials. In study 306, bicalutamide 150-mg monotherapy increased time to objective progression (HR = 0.58; P = 0.033) and treatment failure (HR = 0.66; P = 0.074), whereas in study 307, time to progression (HR = 1.35; P = 0.0471) and treatment failure (HR = 1.24; P = 0.097) favored castration. Bicalutamide therapy showed significant advantages over castration for both sexual interest ( P = 0.029) and physical capacity ( P = 0.046). Bicalutamide 150-mg monotherapy was well tolerated. Conclusions. Bicalutamide 150-mg monotherapy provides a similar survival outcome to castration in previously untreated patients with nonmetastatic advanced prostate cancer and confers statistically significant benefits over castration with respect to sexual interest and physical capacity.