Months Of Androgen Suppression Research Articles

The Relationship between Hot Flashes and Testosterone Recovery after 12 Months of Androgen Suppression for Men with Localised Prostate Cancer in the ASCENDE-RT Trial

AimsThis study describes the proportion of men who experienced hot flashes (flashes), and the testosterone level at onset, peak frequency and cessation of flashes after 12 months of androgen deprivation therapy (ADT) in men undergoing curative-intent external beam radiation therapy (± brachytherapy boost). We also aimed to characterise testosterone recovery in this population. Materials and methodsThis was a pre-specified secondary analysis of the ASCENDE-RT clinical trial. Three hundred and ninety-eight men were randomised. All received 12 months of ADT. The presence and frequency of flashes were patient reported. Cessation of flashes was defined as the first date a patient reported resolution of this symptom. Testosterone recovery was defined as any single serum testosterone above the threshold of 5, 7.5 or 10 nmol/l. ResultsThe median age and follow-up were 68 years and 6.1 years. Flashes were reported in 93% of men. Flashes began and reached peak frequency at a median time of 4.0 months from the first luteinizing hormone-releasing hormone injection when testosterone levels had fallen to castrate. The median time to cessation of flashes was 7.6 months after the cessation of ADT (last injection + 3 months), when the median testosterone had risen to 5.7 nmol/l. A resolution of flashes was reported in 99% of patients. Baseline testosterone was available in 338 patients (85%). The median baseline testosterone was 13.2 nmol/l. The median (95% confidence interval) time of testosterone recovery to thresholds of 5 nmol/l, 7.5 nmol/l and 10 nmol/l were 9 (9–10) months, 13 (10–15) months and 18 (17–19) months from the cessation of ADT. At the time of censor, 96, 94 and 91% of patients had recovered testosterone to thresholds of 5, 7.5 and 10 nmol/l. ConclusionFlashes occur at castrate levels of testosterone, with cessation of hot flashes antedating full recovery of testosterone in most patients. Rates of testosterone recovery after 12 months of ADT exceed 90%, although it can be delayed.

The Relationship Between Hot Flashes and Testosterone Recovery Following 12 Months of Androgen Suppression for Men With Localized Prostate Cancer in a Randomized Trial

The Relationship Between Hot Flashes and Testosterone Recovery Following 12 Months of Androgen Suppression for Men With Localized Prostate Cancer in a Randomized Trial

257: The Relationship Between Hot Flashes and Testosterone Recovery Following 12 Months of Androgen Suppression for Men with Localized Prostate Cancer in the Ascendert Trial

257: The Relationship Between Hot Flashes and Testosterone Recovery Following 12 Months of Androgen Suppression for Men with Localized Prostate Cancer in the Ascendert Trial

Short Androgen Suppression and Radiation Dose Escalation for Intermediate- and High-Risk Localized Prostate Cancer: Results of EORTC Trial 22991.

Up to 30% of patients who undergo radiation for intermediate- or high-risk localized prostate cancer relapse biochemically within 5 years. We assessed if biochemical disease-free survival (DFS) is improved by adding 6 months of androgen suppression (AS; two injections of every-3-months depot of luteinizing hormone-releasing hormone agonist) to primary radiotherapy (RT) for intermediate- or high-risk localized prostate cancer. A total of 819 patients staged: (1) cT1b-c, with prostate-specific antigen (PSA) ≥ 10 ng/mL or Gleason ≥ 7, or (2) cT2a (International Union Against Cancer TNM 1997), with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread, with PSA ≤ 50 ng/mL, were centrally randomized 1:1 to either RT or RT plus AS started on day 1 of RT. Centers opted for one dose (70, 74, or 78 Gy). Biochemical DFS, the primary end point, was defined from entry until PSA relapse (Phoenix criteria) and clinical relapse by imaging or death of any cause. The trial had 80% power to detect hazard ratio (HR), 0.714 by intent-to-treat analysis stratified by dose of RT at the two-sided α = 5%. The median patient age was 70 years. Among patients, 74.8% were intermediate risk and 24.8% were high risk. In the RT arm, 407 of 409 patients received RT; in the RT plus AS arm, 403 patients received RT plus AS and three patients received RT only. At 7.2 years median follow-up, RT plus AS significantly improved biochemical DFS (HR, 0.52; 95% CI, 0.41 to 0.66; P < .001, with 319 events), as well as clinical progression-free survival (205 events, HR, 0.63; 95% CI, 0.48 to 0.84; P = .001). In exploratory analysis, no statistically significant interaction between treatment effect and dose of RT could be evidenced (heterogeneity P = .79 and P = .66, for biochemical DFS and progression-free survival, respectively). Overall survival data are not mature yet. Six months of concomitant and adjuvant AS improves biochemical and clinical DFS of intermediate- and high-risk cT1b-c to cT2a (with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread) prostatic carcinoma, treated by radiation.

EORTC trial 22991: Results of a phase III study comparing 6 months of androgen suppression and irradiation versus irradiation alone for localized T1b-cT2aN0M0 prostate cancer.

22 Background: Up to 30% patients irradiated for intermediate- or high-risk localized prostate cancer experience relapse biochemically within 5 years. We assessed if biochemical disease-free survival (BDFS) is improved by adding 6 months of androgen suppression (AS) – twice 3-month depot LHRH-agonist to primary irradiation (RT) for intermediate or high risk localized T1b-cT2a N0M0 prostate cancer. Methods: 819 patients staged cT1b-c with PSA ≥ 10 ng/ml or Gleason ≥ 7 or cT2a (UICC TNM 1997) N0 M0 with PSA ≤ 50 ng/ml were randomized between RT or RT+ADT. Centers elected one dose of prostate irradiation: 70, 74, or 78 Gy. Irradiation of pelvic nodes was left to the discretion of each institution. The trial aimed to show an increase of +7.5% in 5-year BPFS (HR=0.714) with 80% power. This requires 274 events in intent-to-treat analysis. HRQoL was assessed by EORTC QLQ-C30+PR25 (ClinicalTrials.gov NCT00021450). Results: Patients were 70 y old in median, 88% had WHO PS 0, 74.8% were intermediate risk, and 24.8% high risk. In the RT arm, 407/409 received RT, in the RT+ADT, 403/410 received RT+ AS and 3 RT. Six patients refused treatment. After a median follow-up of 7.2 years, 201 and 118 events for BPFS were observed in the RT and RT+ AS arm. RT+ AS improved BPFS compared to RT (HR=0.53, CI: 0.42-0.67, P&lt;0.001) irrespective of the radiation dose (heterogeneity P&gt;0.1). The 5-y BPFS increased from 69.3% to 82.5%. Clinical PFS was also statistically significantly improved (205 events, HR=0.63, CI: 0.48-0.84, P=0.001, +7.9% at 5 years). Late genitourinary toxicity was reported by 5.9% vs. 3.6% of the patients, on RT+ AS and RT, respectively (p=0.14), whereas 27.0% vs 19.4% reported severe impairment of sexual function (p=0.010). Overall HRQoL did not differ between the groups. Hormonal treatment symptoms, sexual activity and functioning scales are clinically significantly impaired by AS at month 6 and year 1; from year 2 no marked difference is seen. Conclusions: The addition of 6 months of medical castration to primary irradiation improves BPFS and PFS in intermediate- and high-risk localized T1b-cT2a N0M0 prostatic carcinoma with no persistent detriment on HRQoL or sexual function. Clinical trial information: NCT00021450.

Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial

We investigated whether 18 months of androgen suppression plus radiotherapy, with or without 18 months of zoledronic acid, is more effective than 6 months of neoadjuvant androgen suppression plus radiotherapy with or without zoledronic acid. We did an open-label, randomised, 2 × 2 factorial trial in men with locally advanced prostate cancer (either T2a N0 M0 prostatic adenocarcinomas with prostate-specific antigen [PSA] ≥10 μg/L and a Gleason score of ≥7, or T2b-4 N0 M0 tumours regardless of PSA and Gleason score). We randomly allocated patients by computer-generated minimisation--stratified by centre, baseline PSA, tumour stage, Gleason score, and use of a brachytherapy boost--to one of four groups in a 1:1:1:1 ratio. Patients in the control group were treated with neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) for 6 months (short-term) and radiotherapy alone (designated STAS); this procedure was either followed by another 12 months of androgen suppression with leuprorelin (intermediate-term; ITAS) or accompanied by 18 months of zoledronic acid (4 mg every 3 months for 18 months, intravenously; STAS plus zoledronic acid) or by both (ITAS plus zoledronic acid). The primary endpoint was prostate cancer-specific mortality. This analysis represents the first, preplanned assessment of oncological endpoints, 5 years after treatment. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00193856. Between Oct 20, 2003, and Aug 15, 2007, 1071 men were randomly assigned to STAS (n=268), STAS plus zoledronic acid (n=268), ITAS (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 7·4 years (IQR 6·5-8·4). Cumulative incidences of prostate cancer-specific mortality were 4·1% (95% CI 2·2-7·0) in the STAS group, 7·8% (4·9-11·5) in the STAS plus zoledronic acid group, 7·4% (4·6-11·0) in the ITAS group, and 4·3% (2·3-7·3) in the ITAS plus zoledronic acid group. Cumulative incidence of all-cause mortality was 17·0% (13·0-22·1), 18·9% (14·6-24·2), 19·4% (15·0-24·7), and 13·9% (10·3-18·8), respectively. Neither prostate cancer-specific mortality nor all-cause mortality differed between control and experimental groups. Cumulative incidence of PSA progression was 34·2% (28·6-39·9) in the STAS group, 39·6% (33·6-45·5) in the STAS plus zoledronic acid group, 29·2% (23·8-34·8) in the ITAS group, and 26·0% (20·8-31·4) in the ITAS plus zoledronic acid group. Compared with STAS, no difference was noted in PSA progression with ITAS or STAS plus zoledronic acid; however, ITAS plus zoledronic acid reduced PSA progression (sub-hazard ratio [SHR] 0·71, 95% CI 0·53-0·95; p=0·021). Cumulative incidence of local progression was 4·1% (2·2-7·0) in the STAS group, 6·1% (3·7-9·5) in the STAS plus zoledronic acid group, 1·5% (0·5-3·7) in the ITAS group, and 3·4% (1·7-6·1) in the ITAS plus zoledronic acid group; no differences were noted between groups. Cumulative incidences of bone progression were 7·5% (4·8-11·1), 14·6% (10·6-19·2), 8·4% (5·5-12·2), and 7·6% (4·8-11·2), respectively. Compared with STAS, STAS plus zoledronic acid increased the risk of bone progression (SHR 1·90, 95% CI 1·14-3·17; p=0·012), but no differences were noted with the other two groups. Cumulative incidence of distant progression was 14·7% (10·7-19·2) in the STAS group, 17·3% (13·0-22·1) in the STAS plus zoledronic acid group, 14·2% (10·3-18·7) in the ITAS group, and 11·1% (7·6-15·2) in the ITAS plus zoledronic acid group; no differences were recorded between groups. Cumulative incidence of secondary therapeutic intervention was 25·6% (20·5-30·9), 28·9% (23·5-34·5), 20·7% (16·1-25·9), and 15·3% (11·3-20·0), respectively. Compared with STAS, ITAS plus zoledronic acid reduced the need for secondary therapeutic intervention (SHR 0·67, 95% CI 0·48-0·95; p=0·024); no differences were noted with the other two groups. An interaction between trial factors was recorded for Gleason score; therefore, we did pairwise comparisons between all groups. Post-hoc analyses suggested that the reductions in PSA progression and decreased need for secondary therapeutic intervention with ITAS plus zoledronic acid were restricted to tumours with a Gleason score of 8-10, and that ITAS was better than STAS in tumours with a Gleason score of 7 or lower. Long-term morbidity and quality-of-life scores were not affected adversely by 18 months of androgen suppression or zoledronic acid. Compared with STAS, ITAS plus zoledronic acid was more effective for treatment of prostate cancers with a Gleason score of 8-10, and ITAS alone was effective for tumours with a Gleason score of 7 or lower. Nevertheless, these findings are based on secondary endpoint data and post-hoc analyses and must be regarded cautiously. Long- term follow-up is necessary, as is external validation of the interaction between zoledronic acid and Gleason score. STAS plus zoledronic acid can be ruled out as a potential therapeutic option. National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Calvary Health Care (Calvary Mater Newcastle Radiation Oncology Fund), Hunter Medical Research Institute, Maitland Cancer Appeal, Cancer Standards Institute New Zealand.

Quality of life in men with locally advanced prostate cancer treated with leuprorelin and radiotherapy with or without zoledronic acid (TROG 03.04 RADAR): secondary endpoints from a randomised phase 3 factorial trial

Adjuvant androgen suppression and bisphosphonates with escalating doses of radiotherapy might improve efficacy outcomes in men with locally advanced prostate cancer. In this study, we investigated whether these treatments had a detrimental effect on patient-reported-outcome (PRO) scores. We undertook a phase 3 trial with a 2×2 factorial design in 23 centres in Australia and New Zealand in men with non-metastatic adenocarcinoma of the prostate (stage T2b-4 or T2a, Gleason score ≥7, and baseline prostate-specific antigen concentration [PSA] ≥10 μg/L), and without previous lymph node or systemic metastases or comorbidities that could reduce life expectancy to less than 5 years. The men were randomly assigned in a 1:1:1:1 ratio to 6 months of neoadjuvant (short-term) androgen suppression (STAS) with leuprorelin (22·5 mg every 3 months, intramuscularly) or an additional 12 months (intermediate-term androgen suppression [ITAS]) of leuprorelin with or without 18 months of zoledronic acid (4 mg every 3 months, intravenously). Study drug administration commenced at randomisation after which radiotherapy started within the fifth month in all groups. Treatment allocation was open-label, and computer-generated randomisation, stratified by centre, baseline concentrations of PSA, clinical stage of the tumour, Gleason score, and use of a brachytherapy boost, was done by use of the minimisation technique. PRO scores were calculated from European Organization for Research and Treatment of Cancer quality-of-life and prostate-specific quality-of-life module questionnaires and compared with multiple regression models at baseline, and end of radiotherapy, and 18 months and 36 months according to group and radiation dose. The trial is ongoing and the primary endpoint, prostate-cancer-specific mortality, will be reported in 2014. This study is the final report of PRO scores (a secondary endpoint). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00193856. 1071 men were randomly assigned to STAS (n=268), STAS plus zoledronic acid (n=268), ITAS (n=268), and ITAS plus zoledronic acid (n=267). At the end of radiotherapy, significant detrimental changes in PRO scores (p<0·01) occurred in all groups. There were no significant differences in global health status between groups at any timepoint. At 18 months, PROs that were significantly worse in the ITAS groups when compared with STAS were hormone-treatment-related symptoms (HTRS; STAS, 10·20 [95% CI 8·66-11·75]; ITAS, 17·36 [13·63-21·08], p<0·01; and ITAS plus zoledronic acid, 19·14 [15·43-22·85], p<0·01), sexual activity (STAS, 26·38 [23·50-29·27]; ITAS, 14·40 [7·44-21·36], p<0·01; and ITAS plus zoledronic acid, 16·34 [9·39-23·28], p<0·01), social function (STAS, 90·31 [87·89-92·73]; ITAS, 87·35 [81·52-93·18], p=0·09; and ITAS plus zoledronic acid, 83·66 [77·85-89·48], p<0·01), fatigue (STAS, 17·05 [14·58-19·51]; ITAS 24·52 [18·58-30·46], p<0·01; and ITAS plus zoledronic acid, 24·26 [18·33-30·18], p<0·01), and financial problems (STAS, 3·39 [1·29-5·48]; ITAS, 8·97 [3·92-14·02], p<0·01; and ITAS plus zoledronic acid, 8·92 [3·89-13·96], p<0·01). With the exception of HTRS, in which marginal differences remained, persisting significant differences disappeared by 36 months. Other factors associated with significant detrimental changes in PRO scores were a brachytherapy boost, incomplete testosterone and haemoglobin recoveries, age, and smoking. Compared with 6 months of androgen suppression, 18 months of androgen suppression causes additional detrimental changes at the 18 month follow-up in some PRO scores but not in global quality-of-life scores. However, with the exception of HTRS, these differences resolved by 36 months. The use of zoledronic acid every 3 months over 18 months does not result in additional detrimental changes, but the use of a brachytherapy boost to achieve radiation dose escalation in the prostate can adversely affect emotional function and financial problems. National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Radiation Oncology Fund, and Maitland Cancer Appeal.

Outcomes following iodine-125 brachytherapy in patients with Gleason 7, intermediate risk prostate cancer: A population-based cohort study

Background and purposeTo evaluate outcome in patients with Gleason 7 prostate cancer treated with iodine-125 brachytherapy at the British Columbia Cancer Agency. Materials and methodsBetween 20th July 1998 and 7th February 2006, 1500 patients underwent I-125 prostate brachytherapy without supplemental external beam radiation therapy. Of these, 439 had Gleason 7 disease; 362 had Gleason 3+4 and 77 had 4+3 disease. Generally, patients received 6months of androgen suppression. We compared biochemical no evidence of disease (bNED) between patients with Gleason ⩽6 and Gleason 7 and between Gleason 3+4 and 4+3 using the Phoenix definition of biochemical recurrence. ResultsMedian follow-up was 60months. Estimated 5year bNED was 97% for patients with Gleason score ⩽6 and 94% for patients with Gleason 7 disease (p=0.037). Estimated bNED was 95% and 94% for 3+4 and 4+3, respectively (p=0.791). There was no difference in bNED between implants achieving D90⩾versus<the median value (150.5Gy) or⩾versus<140Gy. ConclusionsI-125 brachytherapy with 6months of ADT demonstrates excellent bNED rates in Gleason 7 disease. We found no evidence of a difference between patients with Gleason 3+4 versus 4+3 disease.

Surrogate endpoints for prostate cancer-specific mortality after radiotherapy and androgen suppression therapy in men with localised or locally advanced prostate cancer: an analysis of two randomised trials

Androgen suppression therapy and radiotherapy are used to treat locally advanced prostate cancer. 3 years of androgen suppression confers a small survival benefit compared with 6 months of therapy in this setting, but is associated with more toxic effects. Early identification of men in whom radiotherapy and 6 months of androgen suppression is insufficient for cure is important. Thus, we assessed whether prostate-specific antigen (PSA) values can act as an early surrogate for prostate cancer-specific mortality (PCSM). We systematically reviewed randomised controlled trials that showed improved overall and prostate cancer-specific survival with radiotherapy and 6 months of androgen suppression compared with radiotherapy alone and measured lowest PSA concentrations (PSA nadir) and those immediately after treatment (PSA end). We assessed a cohort of 734 men with localised or locally advanced prostate cancer from two eligible trials in the USA and Australasia that randomly allocated participants between Feb 2, 1996, and Dec 27, 2001. We used Prentice criteria to assess whether reported PSA nadir or PSA end concentrations of more than 0·5 ng/mL were surrogates for PCSM. Men treated with radiotherapy and 6 months of androgen suppression in both trials were significantly less likely to have PSA end and PSA nadir values of more than 0·5 ng/mL than were those treated with radiotherapy alone (p<0·0001). Presence of candidate surrogates (ie, PSA end and PSA nadir values >0·5 ng/mL) alone and when assessed in conjunction with the randomised treatment group increased risk of PCSM in the US trial (PSA nadir p=0·0016; PSA end p=0·017) and Australasian trial (PSA nadir p<0·0001; PSA end p=0·0012). In both trials, the randomised treatment group was no longer associated with PCSM (p ≥ 0·20) when the candidate surrogates were included in the model. Therefore, both PSA metrics satisfied Prentice criteria for surrogacy. After radiotherapy and 6 months of androgen suppression, men with PSA end values exceeding 0·5 ng/mL should be considered for long-term androgen suppression and those with localised or locally advanced prostate cancer with PSA nadir values exceeding 0·5 ng/mL should be considered for inclusion in randomised trials investigating the use of drugs that have extended survival in castration-resistant metastatic prostate cancer. None.

Type I Collagen Synthesis Marker Procollagen I N-Terminal Peptide (PINP) in Prostate Cancer Patients Undergoing Intermittent Androgen Suppression

Intermittent androgen suppression (IAS) therapy for prostate cancer patients attempts to maintain the hormone dependence of the tumor cells by cycles alternating between androgen suppression (AS) and treatment cessation till a certain prostate-specific antigen (PSA) threshold is reached. Side effects are expected to be reduced, compared to standard continuous androgen suppression (CAS) therapy. The present study examined the effect of IAS on bone metabolism by determinations of serum procollagen I N-terminal peptide (PINP), a biochemical marker of collagen synthesis. A total of 105 treatment cycles of 58 patients with prostate cancer stages ≥pT2 was studied assessing testosterone, PSA and PINP levels at monthly intervals. During phases of AS lasting for up to nine months PSA levels were reversibly reduced, indicating apoptotic regression of the prostatic tumors. Within the first cycle PINP increased at the end of the AS period and peaked in the treatment cessation phase. During the following two cycles a similar pattern was observed for PINP, except a break in collagen synthesis as indicated by low PINP levels in the first months off treatment. Therefore, measurements of the serum PINP concentration indicated increased bone matrix synthesis in response to >6 months of AS, which uninterruptedly continued into the first treatment cessation phase, with a break into each of the following two pauses. In summary, synthesis of bone matrix collagen increases while degradation decreases during off-treatment phases in patients undergoing IAS. Although a direct relationship between bone matrix turnover and risk of fractures is difficult to establish, IAS for treatment of biochemical progression of prostate tumors is expected to reduce osteoporosis in elderly men often at high risk for bone fractures representing a highly suitable patient population for this kind of therapy.

A critical analysis of the long-term impact of brachytherapy for prostate cancer: a review of the recent literature

A number of articles have been published in the past several months providing long-term follow-up data on large brachytherapy series from centers of excellence or highly experienced individual practitioners. Our purpose is to review this recent literature and place it in context, especially as compared with notable articles in the recent past that have described less favorable outcomes. A total of 3773 patients were included in three large permanent seed implant studies, the first with almost exclusively low-dose rate permanent seed brachytherapy monotherapy, the second including a large proportion of patients receiving 6 months of androgen suppression, and the third including both supplemental external beam radiotherapy (EBRT) and hormonal therapy. The 7-10 year biochemical no evidence of disease rates ranged from 94 to 95.6%, with the vast majority of patients achieving prostate specific antigen nadirs less than 0.4 ng/ml. Eight to 10 year follow-up on high-dose rate brachytherapy patients treated with combined EBRT and an high-dose rate boost are equally impressive, especially considering that these series contain a large proportion of men with unfavorable disease. Both low-dose rate and high-dose rate prostate brachytherapy, either alone or given as a boost combined with moderate-dose EBRT, provide impressive long-term disease control and may be the optimal form of intraprostatic dose escalation.

Hyperthermia combined with radiation for the treatment of locally advanced prostate cancer

AbstractBACKGROUND:The authors present long‐term results from a phase 2 study that assessed the efficacy of transrectal ultrasound hyperthermia plus radiation with or without androgen suppression for the treatment of locally advanced prostate cancer.METHODS:Patients with clinical T2b‐T3bN0M0 disease (according to 1992 American Joint Committee on Cancer [AJCC] criteria) received radiation plus 2 transrectal ultrasound hyperthermia treatments. After the first 4 patients, 6 months of androgen suppression were allowed. The study was designed to assess absolute improvement in the 2‐year disease‐free survival rate compared with the short‐term androgen suppression arm in Radiation Therapy Oncology Group (RTOG) study 92‐02.RESULTS:Thirty‐seven patients received a total of 72 hyperthermia treatments. The mean cumulative equivalent minutes (CEM) T9043°C was 8.4 minutes. According to the 1992 AJCC classification, there were 19 patients with T2b tumors, 8 patients with T2c tumors, 5 patients with T3a tumors, and 5 patients with T3b tumors. The median Gleason score was 7 (range, 6‐9), and the median prostate‐specific antigen (PSA) level was 13.3 ng/mL (range, 2‐65 ng/mL). Thirty‐three patients received androgen suppression. At a median follow‐up of 70 months (range, 18‐110 months), the 7‐year overall survival rate was 94%, and 61% of patients remained failure free (according to the American Society for Therapeutic Radiology and Oncology definition for failure free survival). The absolute rate of disease‐free survival at 2 years, which was the primary study endpoint, improved significantly (84%) compared with a rate of 64% for similar patients on the 4‐month androgen suppression arm of RTOG 92‐02. When Phoenix criteria (PSA nadir + 2 ng/mL) were used to define biochemical failure, 89% of patients were failure free at 2 years.CONCLUSIONS:Hyperthermia combined with radiation for the treatment of locally advanced prostate cancer appeared to be promising. The current results indicated that further study of hyperthermia for the treatment of prostate cancer with optimal radiation and systemic therapy is warranted. Cancer 2010. © 2010 American Cancer Society.

New evidence in neoplastic and cardiovascular medicine

The researchers of the European Organization for Research and Treatment of Cancer (EORTC), Radiation Oncology Group and Genito-Urinary Tract Cancer Group conducted a trial to investigate if brief-term androgen suppression (radiotherapy and 6 months of androgen suppression) could maintain quality of life and obtain the general survival rate achieved with long-term androgen suppression (radiotherapy and 3 years of androgen suppression) in individuals with locally advanced prostate cancer. Almost 1,000 subjects (970) who had had external-beam radiotherapy and 6 months of androgen suppression were allocated in a random way to two groups, one receiving no other treatment (brief-term suppression, 483 patients) and the other receiving further treatment with a luteinizing hormone-releasing hormone agonist for 2.5 years (longterm suppression, 487 patients). Ninety-eight patients in the long-term group and 132 patients in the brief-term suppression group were died after a follow-up period of 6.4 years, and 29 were died because of prostate cancer in the long-term suppression group, compared to 47 in the brief-term group. The general mortality at 5 years for the long-term suppression group was 15.2%, compared to an overall mortality of 19% in the brief-term suppression group, with an observed hazard ratio of 1.42. Statistically significant differences were documented between the groups with reference to insomnia (P = 0.006), hot flushes (P 0.001) and sexual activity (P 0.001). The authors conclude that in patients with locally advanced prostate tumour radiotherapy and 3 years of androgen suppression achieve higher survival if compared with radiotherapy and 6 months of androgen suppression.

Duration of Androgen Suppression in the Treatment of Prostate Cancer

The combination of radiotherapy plus long-term medical suppression of androgens (> or = 2 years) improves overall survival in patients with locally advanced prostate cancer. We compared the use of radiotherapy plus short-term androgen suppression with the use of radiotherapy plus long-term androgen suppression in the treatment of locally advanced prostate cancer. We randomly assigned patients with locally advanced prostate cancer who had received external-beam radiotherapy plus 6 months of androgen suppression to two groups, one to receive no further treatment (short-term suppression) and the other to receive 2.5 years of further treatment with a luteinizing hormone-releasing hormone agonist (long-term suppression). An outcome of noninferiority of short-term androgen suppression as compared with long-term suppression required a hazard ratio of more than 1.35 for overall survival, with a one-sided alpha level of 0.05. An interim analysis showed futility, and the results are presented with an adjusted one-sided alpha level of 0.0429. A total of 1113 men were registered, of whom 970 were randomly assigned, 483 to short-term suppression and 487 to long-term suppression. After a median follow-up of 6.4 years, 132 patients in the short-term group and 98 in the long-term group had died; the number of deaths due to prostate cancer was 47 in the short-term group and 29 in the long-term group. The 5-year overall mortality for short-term and long-term suppression was 19.0% and 15.2%, respectively; the observed hazard ratio was 1.42 (upper 95.71% confidence limit, 1.79; P=0.65 for noninferiority). Adverse events in both groups included fatigue, diminished sexual function, and hot flushes. The combination of radiotherapy plus 6 months of androgen suppression provides inferior survival as compared with radiotherapy plus 3 years of androgen suppression in the treatment of locally advanced prostate cancer. (ClinicalTrials.gov number, NCT00003026.)

Anti-Mullerian hormone concentrations in androgen-suppressed women with polycystic ovary syndrome

Current data suggest that excessive androgen exposure can lead to the development of polycystic ovaries and polycystic ovary syndrome (PCOS). Anti-Müllerian hormone (AMH) levels reflect the number of small antral follicles in the ovaries and are elevated in PCOS. We hypothesized that protracted reduction of circulating androgens and/or insulin resistance would reduce circulating AMH concentrations in women with PCOS. A prospective, randomized, double-blind 26 week long study was undertaken in 50 women with PCOS. They all received diet and lifestyle counselling, and metformin 850 mg three times daily. Concomitantly, they were randomized to either dexamethasone 0.25 mg daily (n = 25) or placebo (n = 25). Thirty-eight women completed the study. AMH (primary outcome) and other hormone levels were measured at inclusion and after 8 and 26 weeks of treatment. At baseline in univariate regression analyses, AMH levels associated positively with testosterone levels (P = 0.041) and ovarian volume (P = 0.002). In multivariate regression analyses, AMH associated positively with testosterone P = 0.004), and negatively with dehydroepiandrosterone sulphate (DHEAS) (P = 0.001) and C-peptide levels (P = 0.020). Circulating AMH concentrations were unaffected by 6 months of lifestyle counselling with metformin and placebo treatment. AMH levels were also unaffected by 6 months of androgen suppression with dexamethasone in addition. AMH levels in untreated PCOS women associated positively with testosterone, and negatively with DHEAS and C-peptide levels. Six months of androgen suppression by either metformin or low-dose dexamethasone treatment failed to influence circulating AMH levels.

Effet de la suppression androgénique par agonistes de la LH-RH sur les fonctions cognitives de patients atteints de cancer de prostate

To evaluate secondary effects on cognitive functions as memory and attention impairments in men treated by androgen suppression for cancer of prostate. A prospective study on men treated with luteinizing hormone-realising hormone analogues (LH-RH analogues) for cancer of prostate was designed. Eighteen men were evaluated with cognitive tests as Mini Mental State (MMS), memory evaluation (Grober-Buschke, Rey Test), attention and executive test (Trail Making Test and Montgomery Asberg Depression Rating Scale [MADRS]) before beginning androgen suppression. Base line pretreatment assessments of every patient were compared with similar tests after six and 12 months of hormone therapy. On 18 patients, 14 were eligible with pretreatment-median PSA of 22ng/ml (13-659), testosterone of 477ng/dl (398-583), which decreased to 1 and 37ng/dl, respectively. Visual-memory test (Rey test) was significantly improved at M6 (p: 0,001) and M12 (p: 0,02) as was the inversed number-memory test (WAIS) after M6 of androgen suppression and (p: 0,03). After 12 months of androgen suppression, global cognitive performances were preserved. Our results failed to observe impairment of cognitive function. This deserves more important prospective study.

Bone Mineral Density Changes in Patients With Prostate Cancer During the First 2 Years of Androgen Suppression

We characterized bone mineral density changes in patients with prostate cancer on androgen deprivation therapy during the first 2 years of uninterrupted therapy, and identified which location most reflects bone mass loss. Using dual energy x-ray absorptiometry, bone mineral density was prospectively assessed in patients with nonmetastatic prostate cancer at the lumbar spine and femoral neck, Ward's triangle, trochanter and total hip. Measurements were performed at baseline and yearly thereafter in patients on ADT, and at baseline and 1 year in controls (age matched patients with prostate cancer, free of biochemical progression after radical prostatectomy). A total of 62 patients were included in the study, 31 in each group. Median age (70 and 69 years, respectively), mean Gleason score and mean baseline serum testosterone did not significantly differ. Patients receiving ADT experienced a significant bone mass loss at 12 months in all locations, ranging from 2.29% to 5.55% (p <0.001). In contrast, bone mineral density did not change significantly (0.64% to 1.68%) in patients not receiving ADT. In the 20 patients on ADT after 24 months, the second year decrease was not as severe, nor was it significant compared to first year values. The major bone mass loss occurred in Ward's triangle, with decreases of 5.55% at 12 months and 7.05% at 24 months. Bone mineral density decreases during the first 24 months of androgen suppression with the most relevant effect occurring in the first year. Ward's triangle is the axial skeletal site that reflects the major bone mass loss. Because the deleterious impact of long-term androgen suppression on bone mineral density is inversely related to fracture risk and indirectly related to survival in patients with prostate cancer, early diagnosis and prevention of bone mass loss are warranted in these patients.

Decline in urinary retention incidence in 805 patients after prostate brachytherapy: The effect of learning curve?

To evaluate the incidence and factors predictive of acute urinary retention (AUR) in 805 consecutive patients treated with prostate brachytherapy monotherapy and to examine the possible effect of a learning curve. Between July 1998 and November 2002, 805 patients were treated with prostate brachytherapy. Low-risk patients (Gleason Score (GS) < or = 6; prostate specific antigen (PSA) < or = 10, and < or = T2b [UICC 1997]) received implant alone. Patients with prostate volume of 50 cc or more, GS = 7, or PSA = 10 to 15 received 6 months of androgen suppression (AS) with brachytherapy. Patient, treatment, and dosimetric factors examined include baseline prostate symptom score (IPSS), diabetes, vascular disease, PSA, Gleason score, clinical stage, AS, ultrasound planning target volume (PUTV), postimplant prostate volume (obtained with "Day 30" postimplant CT), CT:PUTV ratio (surrogate for postimplant edema), number of seeds, number of needles, number of seeds per needle, dosimetric parameters (V100, V150, and D90), date of implant (learning curve), and implanting oncologists. Univariate and multivariate analyses were carried out. Acute urinary retention in the first 200 patients was 17% vs. 6.3% in the most recently treated 200 patients (p = 0.002). Overall AUR was 12.7%, and prolonged urinary obstruction incidence (> 20 days) was 5%. On multivariate analysis, factors predictive of any AUR include baseline IPSS (p = < 0.004), CT:PUTV ratio (p = < 0.001), PUTV (p = < 0.001), and implant order (learning curve) (p = 0.001). Factors predictive for "prolonged" catheterization (> 20 days) on multivariate analysis include IPSS (p < 0.01), number of needles (p < 0.001), diabetes mellitus (p = 0.048), and CT:PUTV ratio (p < 0.001) Over the years, our AUR rate has fallen significantly (from 17% to 6.3%). On multivariate analysis, highly significant factors include IPSS, PUTV, CT:PUTV ratio (i.e., degree of prostate edema), and order of implant (learning curve). Over the course of the program, we have deliberately reduced the number of needles and OR time per patient, which have potentially minimized intraoperative trauma and may have contributed to less toxicity. A learning curve in prostate brachytherapy programs affect not only the outcome but also the toxicity from the treatment.

Partners assessment of sexual function on androgen suppression (AS) for treatment of biochemical relapse of prostate cancer

8261 Background: AS leads to significant loss in quality of life domains of sexual and intimate relationships for the partner as well as for the patient. Men with biochemical relapse of prostate cancer live for years and therefore, defining the impact of AS on sexuality and intimacy issues of a couple is important for designing future intervention trials aimed at addressing these problems. Methods: Men with biochemical relapse of prostate cancer were entered on a clinical trial of IAS. The patient and his partner each answered questionnaires at baseline and after 9 months of AS. The partner was asked to answer the same questionnaire according to her own perceptions of the answers as they pertained to the patient. Results: 14 men were married, eugonadal, and Caucasian with a median age of 64.5 years (range 51.8 to 77.2). At baseline, 9 men and 11 women reported erectile dysfunction (ED); 9 couples had no sexual activity during the past month. After 9 months of AS, 13 men and 14 women reported ED; 13 couples had no sexual activity in the past month. Conclusions: Not surprisingly, AS adversely impacted sexual desire, overall sexual function and frequency of sexual activity in most patients. One couple maintained sexual activity throughout. However, baseline sexual function was already poor in the majority of patients. This emphasizes the need to assess baseline function and include the couple rather than just the patient in therapeutic strategies aimed at enhancing sexuality and intimacy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi, TAP

Bone mineral density in patients with prostate cancer without bone metastases treated with intermittent androgen suppression

Objectives To evaluate prospectively the effects of intermittent androgen suppression (AS) on bone mineral density (BMD) in patients with prostate cancer without bone metastases. Methods A total of 19 hormone-naive patients with Stage D0 disease were treated with a luteinizing hormone-releasing hormone analog and an antiandrogen for 9 months, after which AS was discontinued. When the prostate-specific antigen level reached a predetermined threshold, AS was restarted. BMD was measured at baseline, after 9 months of AS, and at the end of the first off-treatment period or at 1 year, whichever occurred first. Results Of the 19 patients, 17 had normal BMD at baseline; 2 patients with osteopenia at baseline were excluded from the analysis. All but 1 of the 17 patients with normal baseline BMD experienced a decline in BMD in the lumbar spine or hip, or both, during AS. After 9 months, the mean BMD in these patients had decreased by 4.5% at the lumbar spine ( P = 0.0007) and by 2.5% at the hip ( P = 0.00013). After a median off-treatment period of 7.9 months, the mean change in BMD of the lumbar spine and hip relative to the post-AS values was 1.5% ( P = 0.06) and −0.01% ( P = 0.09), respectively. Conclusions The observed loss of BMD during 9 months of AS is significantly greater than the expected 0.5% to 1% annual loss. Interruption of AS attenuated the rate of bone loss, although full recovery to the baseline BMD was not achieved in all patients. These data suggest that men treated with AS should undergo baseline and periodic follow-up BMD assessments, because significant bone loss can occur during the first 9 months of AS.