Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Randomized study of neoadjuvant testicular androgen ablation therapy before radical prostatectomy in men with clinically localized prostate cancer. Prospective randomized trial comparing flutamide as adjuvant treatment versus observation after radical prostatectomy for locally advanced, lymph node-negative prostate cancer. Report of a multicenter Canadian phase III randomized trial of 3 months vs. 8 months neoadjuvant androgen deprivation before standard-dose radiotherapy for clinically localized prostate cancer. 4-Year follow-up results of a European prospective randomized study on neoadjuvant hormonal therapy prior to radical prostatectomy in T2-3N0M0 prostate cancer. European Study Group on Neoadjuvant Treatment of Prostate Cancer. Neoadjuvant hormone treatment with leuprolide acetate depot 3.75 mg and cyproterone acetate, before radical prostatectomy: a randomized study. Adjuvant estrogen following radiation therapy for stage C adenocarcinoma of the prostate: long-term results of a prospective randomized study. Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial. The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer. Prolonged neoadjuvant combined androgen blockade leads to a further reduction of prostatic tumor volume: three versus six months of endocrine therapy. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. Effects of complete androgen blockade for 12 and 24 weeks on the pathological stage and resection margin status of prostate cancer. Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects. Bicalutamide ('Casodex') 150 mg as adjuvant to radiotherapy in patients with localised or locally advanced prostate cancer: results from the randomised Early Prostate Cancer Programme. Neoadjuvant hormonal therapy: the Canadian experience. Acceptability of short term neo-adjuvant androgen deprivation in patients with locally advanced prostate cancer. The risk of malignancy in the surgical margin at radical prostatectomy reduced almost three-fold in patients given neo-adjuvant hormone treatment. Long-term followup of a randomized trial of 0 versus 3 months of neoadjuvant androgen ablation before radical prostatectomy. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results.
We did a randomised phase III trial comparing external irradiation alone and external irradiation combined with an analogue of luteinising-hormone releasing hormone (LHRH) to investigate the added value of long-term androgen suppression in locally advanced prostate cancer.
                Between 1987 and 1995, 415 patients were randomly assigned radiotherapy alone or radiotherapy plus immediate androgen suppression. Eligible patients had T1-2 tumours of WHO grade 3 or T3-4 N0-1 M0 tumours; the median age of participants was 71 years (range 51-80). In both treatment groups, 50 Gy radiation was delivered to the pelvis over 5 weeks, and 20 Gy over 2 weeks as a prostatic boost. Goserelin (3.6 mg subcutaneously every 4 weeks) was started on the first day of irradiation and continued for 3 years; cyproterone acetate (150 mg orally) was given for 1 month starting 1 week before the first goserelin injection. The primary endpoint was clinical disease-free survival. Analyses were by intention to treat.
                412 patients had evaluable data, with median follow-up of 66 months (range 1-126). 5-year clinical disease-free survival was 40% (95% CI 32-48) in the radiotherapy-alone group and 74% (67-81) in the combined-treatment group (p=0.0001). 5-year overall survival was 62% (52-72) and 78% (72-84), respectively (p=0.0002) and 5-year specific survival 79% (72-86) and 94% (90-98).
                Immediate androgen suppression with an LHRH analogue given during and for 3 years after external irradiation improves disease-free and overall survival of patients with locally advanced prostate cancer. We determined whether 12 weeks of neoadjuvant testicular androgen ablation therapy using a luteinizing hormone-releasing hormone agonist could improve pathological outcomes in men undergoing radical retropubic prostatectomy for clinically localized (stages T1C, T2A and T2B) prostatic carcinoma.
                A total of 56 participants was randomized to receive either monthly injections of a luteinizing hormone-releasing hormone agonist at 4-week intervals followed by radical retropubic prostatectomy (28) or to undergo immediate radical retropubic prostatectomy alone (28). Operations were performed via similar technique and all prostatic specimens were processed histologically in their entirety.
                There was no improvement in pathological outcome using luteinizing hormone-releasing hormone agonist preoperatively compared to surgery alone. Of 28 men undergoing immediate radical retropubic prostatectomy 23 had organ-confined (17) or specimen-confined (6) disease versus 22 of 28 who received luteinizing hormone-releasing hormone neoadjuvant therapy for 12 weeks preoperatively (16 with organ-confined and 6 with specimen-confined disease, p = 1.00). In addition, when the study population was analyzed by pretreatment prostate specific antigen (PSA) levels (10 ng./ml. or less, or greater than 10 ng./ml/) there was also no difference in pathological outcome (p = 0.65 for PSA greater than 10 and p = 0.32 for PSA less than 10).
                Neoadjuvant androgen ablation therapy for 12 weeks before radical prostatectomy in patients with clinically localized adenocarcinoma of the prostate does not result in improved pathological outcomes. To assess the efficacy and the tolerability of flutamide as adjuvant treatment after radical prostatectomy for locally advanced, lymph node-negative prostate cancer.
                Men with locally advanced, lymph node-negative prostate cancer were randomized after radical prostatectomy to receive either flutamide 750mg daily or no adjuvant treatment. Recurrence-free and overall survival were the study end points. Recurrence was defined as a PSA value greater than 5ng/ml or two values greater than 2ng/ml more than three months apart with increasing tendency or three values greater than 1ng/ml more than three months apart with increasing tendency or any clinical recurrence.
                309 patients (157 in the control arm and 152 in the flutamide arm) were eligible for efficacy analysis. The median follow-up was 6.1 years. Recurrence-free survival was better in the flutamide group ( P=0.0041), there was, however, no detectable difference in overall survival ( p=0.92 ). Moreover, there was a considerable toxicity reported in the flutamide group.
                Although having some effect on disease recurrence, adjuvant flutamide treatment does not improve median-term overall survival after radical prostatectomy for locally advanced, lymph node-negative prostate cancer. To evaluate the effect of 3 months vs. 8 months of neoadjuvant hormonal therapy before conventional dose radiotherapy (RT) on disease-free survival using prostate-specific antigen PSA and biopsies as end points for clinically localized prostate cancer.
                Between February 1995 and June 2001, 378 men were randomized to either 3 or 8 months of flutamide and goserelin before conventional-dose RT (66 Gy) at four participating centers. The median patient age was 72 years (range, 50-84 years). The stage distribution was 17% T1c, 35% T2a, 34% T2b-T2c, 13% T3-T4. The Gleason score (GS) was < or =6 in 51%, 7 in 38%, and 8-10 in 11%. The median baseline PSA level was 9.7 ng/mL (range, 1.3-189 ng/mL). Of the 378 men, 26% were low risk (Stage T1c-T2a, GS < or =6, PSA <10 ng/mL), 43% were intermediate risk (Stage T2b or GS 7 or PSA 10-20 ng/mL), and 31% were high risk (Stage T3 or GS 8-10 or PSA >20 ng/mL). The two arms were balanced in terms of age, GS, T stage, risk group, and presenting PSA level. The median follow-up was 44 months (range, 10-84 months), and 361 patients were available for evaluation.
                The 8-month arm achieved a lower PSA level before starting RT (0.37 vs. 0.74 ng/mL, p < or =0.001) and had a greater downsizing of the prostate (mean volume 26.6 cm(3) vs. 30.5 cm(3), p < or =0.001). However, the actuarial freedom from failure rate (biochemical by American Society for Therapeutic Radiology and Oncology definition, local or distant) for the 3-month vs. 8-month arms at 3 years was 66% vs. 68% and by 5 years was 61% vs. 62%, respectively (p = 0.36). No statistically significant difference was noted in the types of failure between the two arms (crude final status): biochemical, 22.2% vs. 22.3%; local, 10.2% vs. 6.5%; and distant, 3.4% vs. 4.4% (p = 0.61). Two-year post-RT biopsies were done in 57% (n = 205). Negative biopsies were obtained in 68% of the 3-month and 77% of the 8-month patients; 18% and 14% had indeterminate biopsies and 14% and 9% were positive for residual cancer (p = 0.34) in the two arms, respectively. The median PSA level for nonfailing patients was 0.50 ng/mL in both the 3-months and 8-month arms. A suggestion of improvement was found in the 8-month arm for disease-free survival at 5 years for high-risk patients (39% vs. 52%) but did not achieve statistical significance.
                A longer period of neoadjuvant hormonal therapy before standard-dose RT does not appear to confer a benefit in terms of disease-free survival or to alter failure patterns. Failure was delayed in the 8-month arm, but this advantage was lost by 5 years of follow-up. A suggestion of benefit was noted with a longer period of hormonal therapy for high-risk patients. To evaluate the long-term effects of 3-month neoadjuvant hormonal treatment in patients treated by radical prostatectomy for locally confined prostate cancer.
                We report the results of 402 patients (220 with a clinical T2 tumor and 182 with a clinical T3 tumor) of whom 192 randomly received neoadjuvant total androgen deprivation using a LHRH analogue (goserelin) plus flutamide for a period of 3 months and 210 underwent radical prostatectomy only.
                'Clinical downstaging' was seen in 30% of cases in the neoadjuvantly treated group (NEO). 'Pathological downstaging' occurred in 7 and 15% of cases in the direct radical prostatectomy (DP) group and the NEO group, respectively (p<0.01). In patients with clinical T2 as well as in patients with clinical T3 tumors, a significant difference in the number of positive margins was shown in favor of the NEO group (cT2, p<0.01; cT3, p = 0.01). This advantage, although there was a trend in favor of the NEO group, specifically in cT2 tumors, did not translate in a significantly better PSA progression rate (p = 0.18). However, when evaluating the local control rate in cT2 tumors, we observed local recurrence in 3 of 102 (3%) patients in the NEO group versus 12 of 114 (11%) patients in the DP group. The difference is statistically significant (p = 0.03). In the cT3 group, this difference was not statistically significant (NEO group: 15 of 87 (17%), and DP group: 21 of 95 (22%) patients; p = 0.41).
                In this study, the clinical revelance of pathological downstaging and the lower percentage of patients with positive margins in the neoadjuvantly treated group with a clinical T2 tumor is not confirmed by a lower PSA progression rate. However, this study indicates that there may be a trend that this advantage in favor of the NEO group directly translates into a better local control rate in clinical T2 tumors. Better local control in cT2 tumors is only going to be of relevance if subsequently you can show that there is a better survival for these patients. Unfortunately, this article reports a study which is not yet mature enough to show relevant information. Presently, neoadjuvant therapy should not be given outside clinical research settings. To assess the effect of neoadjuvant hormone treatment before radical prostatectomy on: tumor/prostate volume, prostate-specific antigen (PSA) and testosterone levels, surgical margin status and tumor stage, and the ease of surgery following treatment.
                Patients with clinically localized prostatic carcinoma were randomized to receive leuprolide acetate depot 3.75 mg once a month for 3 months and cyproterone acetate 300 mg once a week for 3 weeks prior to surgery (group A). A control group of patients had surgery without any pretreatment (group B).
                167 patients were evaluated for the efficacy parameters. In group A, 31% of patients had a reduction in tumor/prostate volume following hormone therapy. PSA and testosterone levels were significantly reduced (p = 0.0001) in patients in group A compared to basal values. Centralized histopathological data evaluated in 145 patients (group A and 75 group B) showed that more patients in group B had tumors at stages T3A and T3B than in group A; this difference was close to significance (p = 0.057). Positive surgical margins were more common in group B (60% of patients) compared to group A (39% of patients). Similarly lymph node involvement was more common in group B compared to group A (11 versus 3%). There was little difference between the 2 study groups for the other surgical parameters assessed (ease of dissection, duration of surgery, blood loss).
                Neoadjuvant hormone therapy before radical prostatectomy has some effects in the treatment of prostate cancer. However, long-term follow-up of patients is needed to assess the impact of this therapy on morbidity and mortality.
                Copyright 2004 S. Karger AG, Basel Seventy-eight patients with clinical Stage C adenocarcinoma of the prostate were prospectively randomized to receive either radiation alone or radiation and adjuvant estrogen (diethylstilbestrol). No patient had received any prior definitive treatment for cancer. Forty patients were randomized to receive radiotherapy only and 38 patients to receive radiotherapy and estrogen. The median follow-up for all surviving patients was 14.5 years. Whether analyzed according to the original randomization or according to the treatment actually received, disease-free survival in the adjuvant estrogen group was strikingly and significantly higher than in the radiation-only group. At 5, 10, and 15 years patients receiving adjuvant estrogen had respective disease-free survival rates of 71%, 63%, and 63% compared with 49%, 43%, and 35% in patients having radiation only (p = 0.008). However, because of greater intercurrent disease-related mortality in patients receiving estrogen, there was no improvement in survival. This study suggests that a prospective randomized evaluation of early androgen deprivation with orchiectomy or with one of the nonestrogenic agents should be undertaken and that patients receiving early androgen deprivation should not be included in series reporting on the curative potential of radiation as a single modality. To test the hypothesis that androgen ablation before and during radiotherapy for locally advanced carcinoma of the prostate may, by reducing tumor bulk and enhancing tumor cell kill, improve locoregional control and ultimately survival.
                The study was conducted from 1987 to 1991. Eligible patients were those with bulky tumors (T2--T4) with or without pelvic lymph node involvement and without evidence of distant metastases. They were randomized to receive goserelin, 3.6 mg every 4 weeks; and flutamide, 250 mg t.i.d. for 2 months before radiation therapy and during radiation therapy (Arm I), or radiation therapy alone (Arm II). Of 471 randomized patients, 456 were evaluable: 226 on Arm I and 230 on Arm II.
                As of November 1999, the median follow-up has reached 6.7 years for all patients and 8.6 years for alive patients. At 8 years, androgen ablation has been associated with an improvement in local control (42% vs. 30%, p = 0.016), reduction in the incidence of distant metastases (34% vs. 45%, p = 0.04), disease-free survival (33% vs. 21%, p = 0.004), biochemical disease-free survival = PSA <1.5 (24% vs. 10%, p < 0.0001), and cause-specific mortality (23% vs. 31%, p = 0.05). However, subset analysis indicates that the beneficial effect of short-term androgen ablation appears preferentially in patients with Gleason score 2--6. In that population, there is a highly significant improvement in all endpoints, including survival (70% vs. 52%, p = 0.015). In patients with Gleason 7--10 tumors, the regimen has not resulted in a significant enhancement in either locoregional control or survival.
                In patients with Gleason score 2--6 carcinoma of the prostate, a short course of androgen ablation administered before and during radiotherapy has been associated with a highly significant improvement in local control, reduction in disease progression, and overall survival. Radiation Therapy Oncology Group protocol 85-31 was designed to evaluate the effectiveness of adjuvant androgen suppression, using goserelin, in unfavorable prognosis carcinoma of the prostate treated with definitive radiotherapy (RT).
                Eligible patients were those with palpable primary tumor extending beyond the prostate (clinical Stage T3) or those with regional lymphatic involvement. Patients who had undergone prostatectomy were eligible if penetration through the prostatic capsule to the margin of resection and/or seminal vesicle involvement was documented histologically. Stratification was based on histologic differentiation, nodal status, acid phosphatase status, and prior prostatectomy. The patients were randomized to either RT and adjuvant goserelin (Arm I) or RT alone followed by observation and application of goserelin at relapse (Arm II). In Arm I, the drug was to be started during the last week of RT and was to be continued indefinitely or until signs of progression.
                Between 1987 and 1992, when the study was closed, 977 patients were entered: 488 to Arm I and 489 to Arm II. As of July 2003, the median follow-up for all patients was 7.6 years and for living patients was 11 years. At 10 years, the absolute survival rate was significantly greater for the adjuvant arm than for the control arm: 49% vs. 39%, respectively (p = 0.002). The 10-year local failure rate for the adjuvant arm was 23% vs. 38% for the control arm (p <0.0001). The corresponding 10-year rates for the incidence of distant metastases and disease-specific mortality was 24% vs. 39% (p <0.001) and 16% vs. 22% (p = 0.0052), respectively, both in favor of the adjuvant arm.
                In a population of patients with unfavorable prognosis carcinoma of the prostate, androgen suppression applied as an adjuvant after definitive RT was associated not only with a reduction in disease progression but in a statistically significant improvement in absolute survival. The improvement in survival appeared preferentially in patients with a Gleason score of 7-10. Androgen deprivation is an established treatment regimen for disseminated prostate cancer; however, its role in patients with localised cancer is less clear. We did a large randomised controlled trial to determine whether 3 months or 6 months of androgen deprivation given before and during radiotherapy improves outcomes for patients with locally advanced prostate cancer.
                818 men with locally advanced prostate cancer were randomly assigned to: no androgen deprivation (ie, radiotherapy alone: 66 Gy in 33 fractions of 2 Gy per day over 6.5-7.0 weeks to the prostate and seminal vesicles); 3 months' androgen deprivation with 3.6 mg goserelin given subcutaneously every month and 250 mg flutamide given orally three times a day starting 2 months before radiotherapy (same regimen as control group); or 6 months' androgen deprivation, with the same regimen, starting 5 months before radiotherapy (same regimen as control group). Primary endpoints were time to local failure and prostate-cancer-specific survival; secondary endpoints were distant failure, disease-free survival, and freedom from salvage treatment. Analyses were done by intention to treat.
                802 (98%) patients were eligible for analysis. Median follow-up was 5.9 years (range 0.1-8.5). Compared with patients assigned no androgen deprivation, those assigned 3 months' treatment had significantly improved local failure (hazard ratio [HR] 0.56 [95% CI 0.39-0.79], p=0.001), biochemical failure-free survival (0.70 [0.56-0.88], p=0.002), disease-free survival (0.65 [0.52-0.80], p=0.0001), and freedom from salvage treatment (0.73 [0.56-0.96], p=0.025). 6 months' androgen deprivation significantly improved local failure (0.42 [0.28-0.62], p<0.0001), biochemical failure-free survival (0.58 [0.46-0.74], p<0.0001), disease-free survival (0.56 [0.45-0.69], p<0.0001), freedom from salvage treatment (0.53 [0.40-0.71], p<0.0001), distant failure (0.67 [0.45-0.99], p=0.046) and prostate-cancer-specific survival (0.56 [0.32-0.98], p=0.04) compared with no androgen deprivation.
                6 months' androgen deprivation given before and during radiotherapy improves the outlook of patients with locally advanced prostate cancer. Further follow-up is needed to estimate precisely the size of survival benefits. Increased radiation doses and additional periods of androgen deprivation might lead to further benefit. We evaluated the benefits and sequencing of androgen suppression (AS) administered with external beam radiation therapy (EBRT) in T2-T3 prostate cancers.
                Between 1990 and 1999, 481 patients were entered in 2 successive, prospective, randomized studies, including 161 in the study 1 and 325 in study 2. Eligible patients had clinical stages T2-T3 prostate cancer. In the first study (L-101) subjects were randomly allocated among EBRT alone (group 1), EBRT preceded by 3 months of AS (group 2), and neoadjuvant, concomitant and adjuvant AS for a total of 10 months (group 3). In the second study (L-200) we analyzed neoadjuvant and concomitant AS (total 5 months) vs neoadjuvant, concomitant and short course adjuvant (total 10 months) AS with EBRT. In each study we used a total AS (a luteinizing hormone-releasing hormone agonist plus an antiandrogen) and a standard dose of radiation therapy at that time. Patient characteristics were well balanced in regard to age, stage, prostate specific antigen and Gleason score. No biochemical evidence of disease (BNED) was defined as an end point according to the Vancouver rule.
                In the study 1 at a median followup of 5 years 7-year biochemical-free survival rates were 42%, 66% and 69% in groups 1 to 3, respectively. BNED was significantly different between groups 1 and 2 (p = 0.009) and between groups 1 and 3 (p = 0.003) but not between groups 2 and 3 (p = 0.6). Multivariate analysis using a Cox proportional hazards model showed an HR of 6.1 for Gleason score (p = 0.001), 1.4 for PSA (p = 0.002), 0.5 for group 1 vs group 2 (p = 0.01) and 0.35 for group 1 vs group 3 (p = 0.008). In study 2 BNED at 4 years was 65%. There was no significant difference between arms 1 and 2 (p = 0.55).
                The analysis of study 1 shows a benefit of using a short course of neoadjuvant AS with EBRT vs EBRT alone for localized T2-T3 prostate cancers. Moreover, in each study adding a short course of adjuvant AS after neoadjuvant 1 provided no more advantage in these patients. In most clinical trials that have investigated the potential beneficial effects of neoadjuvant combined androgen blockade (CAB) in clinically localized prostate cancer, CAB has been given for 3 months, but no data are available on the influence of a longer duration of neoadjuvant CAB on the pathologic features of prostate cancer.
                Prostatectomy specimens of 40 patients, randomized to 3 (n = 18) or 6 (n = 22) months of neoadjuvant CAB, were blindly evaluated with regard to tumor volume, pathologic stage, and surgical margins. The morphologically most vital tumor areas were investigated for nucleolar size and MIB-1 defined proliferative activity.
                The patients treated for 6 months had a median tumor volume 60% lower than the 3-month treatment group (P = 0.005). In the 6-month treatment group, no residual tumor could be found in 2 cases, but the proportion of prostatectomy specimens with seminal vesical invasion and positive surgical margins was not statistically different from that after 3 months. Compared with untreated controls, tumor proliferative activity assessed by MIB-1 immunoreactivity was significantly lower at 3 and 6 months of neoadjuvant CAB (P = 0.01). However, in 2 of 1 7 examined tumors that had been treated for 6 months, high MIB-1 scores suggested a development toward therapy-resistant cancer.
                Prolonged neoadjuvant CAB for 6 months leads to a further decrease in prostatic tumor volume compared with the findings after 3 months. In a few instances, residual tumor areas with substantial MIB-1 defined proliferative activity persist at 6 months, thus indicating that in at least some cases, despite the overall decrease in tumor size, cancer cells can continue the cell cycle under CAB. Because the optimal timing of the institution of antiandrogen therapy for prostate cancer is controversial, we compared immediate and delayed treatment in patients who had minimal residual disease after radical prostatectomy.
                Ninety-eight men who underwent radical prostatectomy and pelvic lymphadenectomy and who were found to have nodal metastases were randomly assigned to receive immediate antiandrogen therapy, with either goserelin, a synthetic agonist of gonadotropin-releasing hormone, or bilateral orchiectomy, or to be followed until disease progression. The patients were assessed quarterly during the first year and then semiannually.
                After a median of 7.1 years of follow-up, 7 of 47 men who received immediate antiandrogen treatment had died, as compared with 18 of 51 men in the observation group (P=0.02). The cause of death was prostate cancer in 3 men in the immediate-treatment group and in 16 men in the observation group (P<0.01). At the time of the last follow-up, 36 men in the immediate-treatment group (77 percent) and 9 men in the observation group (18 percent) were alive and had no evidence of recurrent disease, including undetectable serum prostate-specific antigen levels (P<0.001). In the observation group, the disease recurred in 42 men; 13 of the 36 who were treated had a complete response to local treatment or hormonal therapy (or both), 16 died of prostate cancer, and 1 died of another disease. The remaining men in this group were alive with progressive disease at the time of the last follow-up or had had a recent relapse. Except for the treatment group (immediate therapy or observation), no clinical or histologic characteristic significantly influenced the outcome.
                Immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node-positive prostate cancer. To compare the pathological stage and surgical margin status in patients undergoing either immediate radical prostatectomy or 12 and 24 weeks of neoadjuvant hormonal treatment (NHT) in a prospective, randomised study.
                Whole mount sections of 393 radical prostatectomy specimens were evaluated: 128 patients had immediate surgery, 143 were treated for 12 weeks and 122 for 24 weeks with complete androgen blockade.
                Histopathology revealed organ confined tumours in 40.4% of patients with clinical stage B disease in the immediate surgery group, whereas 12 and 24 weeks of NHT increased the number of organ confined tumours to 54.6% and 64.8%, respectively. Among patients with clinical stage C tumours, pathological staging found organ confined disease in 10.4%, 31.4%, and 61.2% in the immediate surgery, 12 weeks of NHT, and 24 weeks of NHT groups, respectively. Preoperative NHT caused a significant decrease in positive margins both in patients with clinical stage B and C disease. The extent of margin involvement was not influenced by preoperative treatment.
                Neoadjuvant androgenic suppression is effective in reducing both the pathological stage and the positive margin rate in patients with stage B and C prostatic cancer undergoing radical surgery. Some beneficial effects are evident in those patients treated for 24 weeks, and it is reasonable to assume that the optimal duration of NHT is longer than three months. A prospective phase 3 trial was initiated to determine whether 8 compared with 3-month neoadjuvant hormonal therapy reduces prostate specific antigen (PSA) recurrence rates after radical prostatectomy. Our interim analysis includes secondary end points of differences in biochemistry, pathology and adverse events between the 2 groups.
                Men with clinically confined prostate cancer were randomized to receive 7.5 mg. leuprolide intramuscularly monthly and 250 mg. flutamide orally 3 times daily for 3 or 8 months before radical prostatectomy. Our study was powered to detect a 35% decrease in PSA recurrence, assuming a 30% recurrence rate in the 3-month arm after 3 years.
                A total of 547 men were randomized between August 1995 and April 1998. Men in the 8 and 3-month groups were equally stratified for T stage (29% T1c, 70% T2), Gleason grade (68% less than 4, 32% 4 or greater) and pretreatment PSA (63% less than 10, 27% 10 to 20 and 10% greater than 20 microg./l.). Mean pretreatment PSA was slightly higher in the 8-month compared with the 3-month group (11.64 versus 9.95 microg./l., respectively, p = 0.0539). A total of 44 men withdrew from study before surgery and, therefore, were nonevaluable. Preoperative PSA nadir was less than 0.1 microg./l. in 43.3% versus 75.1% (p <0.0001), and 0.3 microg./l. or greater in 21% versus 9.2% after 3 versus 8 months, respectively (p <0.0006). Mean serum PSA decreased 98% to 0.12 microg./l. after 3 months, with a further 57% to 0.052 microg./l. from 3 to 8 months. Transrectal ultrasound determined that prostatic volume decreased 37% from a mean of 40.6 to 25.4 cc after 3-month neoadjuvant hormonal therapy (p = 0.0001) and a further 13% to 22.2 cc after 8 months (p = 0.03). Mean hemoglobin decreased 15% (148.2 to 125.4 gm./dl.) after 3-month neoadjuvant hormonal therapy but stabilized thereafter. Radical prostatectomy was completed in 500 men, while surgery was aborted intraoperatively in 3. Positive margin rates were significantly lower in the 8 than 3-month group (12% versus 23%, respectively, p = 0.0106). There were no fatal adverse events and no differences between the 2 groups in the severity or causality (p = 0.287, 0.0564) of adverse events, or incidence of increased liver enzymes or diarrhea (p = 0.691, 0.288, respectively). However, men in the 8-month group noticed a higher number of newly reported adverse events (4.5 versus 2.9, p <0.0001) and higher incidence of hot flushes than the 3-month group (87% versus 72%, respectively, p <0.0001).
                Ongoing biochemical and pathological regression of prostate tumors occurs between 3 and 8 months of neoadjuvant hormonal therapy, suggesting that the optimal duration of neoadjuvant hormonal therapy is longer than 3 months. Longer followup is needed to determine whether longer therapy alters PSA recurrence rates. The ongoing Early Prostate Cancer (EPC) programme is assessing bicalutamide ('Casodex') 150 mg, either alone or as adjuvant to treatment of curative intent, in patients with localised or locally advanced prostate cancer (n=8113). This paper presents an exploratory analysis of the subgroup of the EPC programme who received radiotherapy with curative intent (n=1370) in order to determine the efficacy (in terms of progression-free survival [PFS]) and tolerability of bicalutamide 150 mg in this setting.
                1370 patients with T1-4, MO, any N prostate cancer received bicalutamide 150 mg or placebo adjuvant to radiotherapy of curative intent. This analysis was undertaken at median 5.3 years' follow-up.
                In patients with locally advanced disease (n=305), bicalutamide adjuvant to radiotherapy significantly increased PFS by 53% (event-time ratio 1.53; 95% confidence intervals [CI] 1.16, 2.02) compared with placebo and reduced the risk of disease progression by 42% (hazard ration [HR] 0.58; 95% CI 0.41, 0.84; P=0.00348). In these patients, objective progression was experienced by 33.5% of those randomised to bicalutamide versus 48.6% for those randomised to placebo. The between-group difference in patients with localised disease (n=1065) failed to reach statistical significance (HR 0.80; 95% CI 0.62, 1.03; P=0.088). The most common adverse events were breast pain (74.8%) and gynaecomastia (66.6%), which were mild to moderate in >90% of cases.
                Bicalutamide 150 mg/day given as adjuvant to radiotherapy significantly improved PFS in patients with locally advanced prostate cancer. For patients with localised disease, the results at this stage from the radiotherapy subgroup and the overall EPC programme suggest that adjuvant hormonal therapy is currently not appropriate. There were no unexpected tolerability findings. To assess the effect of neoadjuvant combination therapy with the antiandrogen flutamide and a luteinizing-hormone-releasing hormone (LHRH) agonist administered for 3 months before radical prostatectomy, compared with surgery alone in early stage prostate cancer on histopathologic findings at surgery and serum prostate-specific antigen (PSA).
                A sample of 161 randomly screened patients diagnosed as having stage B (134 patients) or C (27 patients) prostate cancer were randomly assigned to radical prostatectomy alone or to 3 months of neoadjuvant combination therapy with the antiandrogen flutamide and an LHRH agonist before radical prostatectomy.
                Neoadjuvant combination therapy before radical prostatectomy decreased cancer-positive surgical margins from 33.8% in the control group to only 7.8%, thus leaving 92.2% of patients with negative margins at surgery. A net 54% improvement of staging was observed in favor of combination therapy. Organ-confined disease, on the other hand, increased from 49.3% to 77.8% of patients after 3 months of combination therapy, for a 57.8% increase in the incidence of organ-confined disease. No cancer was found in 6 (6.7%) prostatectomy specimens from the treated group. A close correlation was found between serum PSA at diagnosis and the stage of the disease at surgery. Upstaging increased from 30% at serum PSA values of 0 to 3.0 ng/mL up to 100% at serum PSA values above 15 ng/mL.
                Although long-term follow-up of these patients is required to determine the impact on survival, the marked influence of neoadjuvant combination therapy on the stage of the disease suggests the possibility of a major improvement in the morbidity and mortality from prostate cancer. To determine the acceptability of short term neo-adjuvant maximal androgen deprivation (MAD) to patients treated with external beam radiation for locally advanced prostate cancer.
                Between 1996 and 2000, 818 patients with locally advanced, but non-metastatic, prostate cancer were entered into a randomised clinical trial (TROG 96.01), which compared radiation treatment alone with the same radiation treatment and 3 or 6 months neo-adjuvant MAD with goserelin and flutamide. Relevant symptoms, and how troublesome they were to the patient, were scored using a self-assessment questionnaire. This was completed by the patient at registration, and at specified times during and after treatment. Patients taking flutamide had liver function tests checked at regular intervals.
                All patients have completed at least 12 months follow-up after treatment. Nearly all patients completed planned treatment with goserelin, but 27% of patients in the 6-month MAD treatment arm, and 20% in the 3-month arm, had to stop flutamide early. This was mainly due to altered liver function (up to 17% patients) and bowel side effects (up to 8% patients). However, although flutamide resulted in more bowel symptoms for patients on MAD, there was significant reduction in some urinary symptoms on this treatment. Acute bowel and urinary side effects at the end of radiation treatment were similar in all treatment arms. Side effect severity was unrelated to radiation target volume size, which was reduced by MAD, but symptomatology prior to any treatment was a powerful predictor. Of the 36% of patients who were sexually active before any treatment, the majority became inactive whilst on MAD. However, sexual activity at 12 months after radiation treatment was similar in all treatment arms, indicating that the effects of short term MAD on sexual function are reversible.
                Despite temporary effects on sexual activity, and compliance difficulties with flutamide, short-term neo-adjuvant MAD was not perceived by patients to be a major inconvenience. If neo-adjuvant MAD in the way tested can be demonstrated to lead to improved biochemical control and/or survival, then patients would view these therapeutic gains as worthwhile. Compliance with short-term goserelin was excellent, confirming that LH-RH analogues have a potential role in more long-term adjuvant treatment. However, for more protracted androgen deprivation, survival advantages and deleterious effects need to be assessed in parallel, in order to determine the optimal duration of treatment. To investigate the outcome of neo-adjuvant hormone treatment before radical prostatectomy regarding local tumour extension, peri-operative blood loss and operation time.
                Of 111 surgically treated patients with prostate cancer (T1b-T3a, N0, M0, G1-3), 55 were randomised to immediate radical prostatectomy and 56 to 3 months of neo-adjuvant treatment with triptorelin (3.75 mg i.m. every 28 days) and cyproterone acetate (50 mg b.i.d. for 3 weeks to prevent flare).
                No differences were found in blood loss or operation time but patients who had neo-adjuvant treatment had a significantly lower frequency of positive margins (41 vs. 23%, p = 0.013). Conclusion: Neo-adjuvant treatment does not facilitate radical prostatectomy but may improve the chance of local cure. This must, however, be documented with long-term follow-up in randomised patients. In 1992 we initiated a national randomized prospective trial of 3 months of cyproterone acetate before radical prostatectomy compared to prostatectomy alone. Initial results indicated a 50% decrease in the rate of positive surgical margins. This decrease did not translate into a difference in prostate specific antigen (PSA) progression at 3 years. This report is on the long-term outcome (median followup 6 years) of this cohort.
                This prospective, randomized, open label trial compared 100 mg cyproterone acetate 3 times daily for 3 months before surgery to surgery alone. Randomization occurred between January 1993 and April 1994. Patients were stratified according to clinical stage, baseline serum PSA and Gleason sum. A total of 213 patients were accrued. Biochemical progression was defined as 2 consecutive detectable PSAs (greater than 0.2 ng/ml) at least 4 weeks apart, re-treatment or death from prostate cancer.
                A total of 34 (33.6%) patients undergoing surgery only and 42 (37.5%) patients given neoadjuvant hormone therapy (NHT) had biochemical recurrence during the median followup of 6 years. Despite the significant pathological down staging in this study, there was no significant difference in number of patients with no evidence of biochemical disease (bNED) survival (p = 0.732). A bNED survival benefit favoring NHT was seen in men with a baseline PSA greater than 20 (p = 0.015).
                After 6 years of followup there was no overall benefit with 3 months of NHT. Improved bNED survival was seen in the highest risk PSA group (PSA greater than 20). The possibility that high risk patients may benefit from NHT warrants further investigation. In the initial report of the Lupron Depot Neoadjuvant Prostate Cancer Study Group patients who received 3 months of androgen deprivation had a significant decrease in the positive margin rate. We monitored these patients for 5 years and to our knowledge present the longest followup of any neoadjuvant trial.
                A multi-institutional prospective randomized trial was performed between February 1992 and April 1994 involving patients with stage cT2b prostate cancer, including 138 who received 3 months of leuprolide plus flutamide before radical prostatectomy and 144 who underwent radical prostatectomy only. Patients were followed every 6 months with serum prostate specific antigen (PSA) testing for 5 years. Biochemical recurrence was defined as PSA greater than 0.4 ng./ml.
                At 5 years there was no difference in the biochemical recurrence rate. PSA was less than 0.4 ng./ml. in 64.8% of the patients in the neoadjuvant androgen ablation plus prostatectomy and 67.6% in the prostatectomy only group (p = 0.663).
                Although 3 months of androgen deprivation before radical prostatectomy resulted in an apparently significant decrease in positive surgical margins, a 5-year followup does not indicate any difference in the recurrence rate. Until studies document improvement in biochemical or clinical recurrence with longer periods of treatment, induction androgen deprivation before radical prostatectomy is not indicated.
Hormone therapy combined with either prostatectomy or radiotherapy is associated with significant clinical benefits in patients with local or locally advanced prostate cancer. Significant local control may be achieved when given prior to prostatectomy or radiotherapy, which may improve patient's quality of life. When given adjuvant to these primary therapies, hormone therapy, not only provides a method for local control, but there is also evidence for a significant survival advantage. However, hormone therapy is associated with significant side effects, such as hot flushes and gynaecomastia, as well as cost implications. The decision to use hormone therapy should, therefore, be taken at a local level, between the patient, clinician and policy maker, taking into account the clinical benefits, toxicity and cost. More research is needed to guide the choice, the duration, and the schedule of hormonal deprivation therapy, and the impact of long-term hormone therapy with regard to toxicity and the patient's quality of life.