Duration Of Neoadjuvant Hormonal Therapy Research Articles

Predictors of prostate volume reduction following neoadjuvant cytoreductive androgen suppression.

PurposeLimited duration cytoreductive neoadjuvant hormonal therapy (NHT) is used prior to definitive radiotherapeutic management of prostate cancer to decrease prostate volume. The purpose of this study is to examine the effect of NHT on prostate volume before permanent prostate brachytherapy (PPB), and determine associated predictive factors.Material and methodsBetween June 1998 and April 2012, a total of 1,110 patients underwent PPB and 207 patients underwent NHT. Of these, 189 (91.3%) underwent detailed planimetric transrectal ultrasound before and after NHT prior to PPB. Regression analysis was used to assess predictors of absolute and percentage change in prostate volume after NHT.ResultsThe median duration of NHT was 4.9 months with inter quartile range (IQR), 4.2-6.6 months. Prostate-specific antigen (PSA) reduced by a median of 97% following NHT. The mean prostate volume before NHT was 62.5 ± 22.1 cm3 (IQR: 46-76 cm3), and after NHT, it was 37.0 ± 14.5 cm3 (IQR: 29-47 cm3). The mean prostate volume reduction was 23.4 cm3 (35.9%). Absolute prostate volume reduction was positively correlated with initial volume and inversely correlated with T-stage, Gleason score, and NCCN risk group. In multivariate regression analyses, initial prostate volume (p < 0.001) remained as a significant predictor of absolute and percent prostate volume reduction. Total androgen suppression was associated with greater percent prostate volume reduction than luteinizing hormone releasing hormone agonist (LHRHa) alone (p = 0.001).ConclusionsProstate volume decreased by approximately one third after 4.9 months of NHT, with total androgen suppression found to be more efficacious in maximizing cytoreduction than LHRHa alone. Initial prostate volume is the greatest predictor for prostate volume reduction.

Inhibition of Pten deficient Castration Resistant Prostate Cancer by Targeting of the SET - PP2A Signaling axis.

The PP2A signaling axis regulates multiple oncogenic drivers of castration resistant prostate cancer (CRPC). We show that targeting the endogenous PP2A regulator, SET (I2PP2A), is a viable strategy to inhibit prostate cancers that are resistant to androgen deprivation therapy. Our data is corroborated by analysis of prostate cancer patient cohorts showing significant elevation of SET transcripts. Tissue microarray analysis reveals that elevated SET expression correlates with clinical cancer grading, duration of neoadjuvant hormone therapy (NHT) and time to biochemical recurrence. Using prostate regeneration assays, we show that in vivo SET overexpression is sufficient to induce hyperplasia and prostatic intraepithelial neoplasia. Knockdown of SET induced significant reductions in tumorgenesis both in murine and human xenograft models. To further validate SET as a therapeutic target, we conducted in vitro and in vivo treatments using OP449 - a recently characterized PP2A-activating drug (PAD). OP449 elicits robust anti-cancer effects inhibiting growth in a panel of enzalutamide resistant prostate cancer cell lines. Using the Pten conditional deletion mouse model of prostate cancer, OP449 potently inhibited PI3K-Akt signaling and impeded CRPC progression. Collectively, our data supports a critical role for the SET-PP2A signaling axis in CRPC progression and hormone resistant disease.

Gleason grading after neoadjuvant hormonal therapy retains prognostic value for systemic progression following radical prostatectomy.

The Gleason grading system in prostatectomy specimens following receipt of neoadjuvant therapy has been considered inaccurate. However, with continuing expansion of novel therapeutics, it is important to understand whether the Gleason system can be effectively utilized in this setting. The aim of this study was to assess the ability of the Gleason grading system to predict systemic progression among prostatectomy specimens treated with neoadjuvant hormone therapy (NHT). This was a single-institution retrospective analysis from 1987 to 2009 of 13,427 patients who underwent radical prostatectomy (RP) without NHT and 1148 patients with NHT. NHT consisted of leuprolide alone (n = 415), antiandrogen therapy alone (n = 400) and combined treatment (n = 333). Kaplan-Meier analysis estimated 15-year systemic progression-free survival among NHT and non-NHT patients. Cox proportional hazard regression models estimated risk of systemic progression following RP according to NHT use and nonuse. Median duration of NHT was 3 months (interquartile range (IQR) 2-4) whereas median follow-up after RP was 8.3 years (IQR 5-10.8). NHT patients were more likely to be D'Amico high risk, have locally advanced pathologic T stage (≥ pT3), pathologic Gleason scores (GS) of 8-10 and lymph node involvement (P<0.0001 for all). NHT use was associated with lower rates of positive surgical margins, more downgrading to pT0 and less GS upgrading from biopsy (P ≤ 0.001 for all). GS could not be assigned to only 3% of NHT patients. On multivariate analysis, pathologic GS remained a predictor of systemic progression (SP) following NHT (hazard ratio (HR) 1.6, P = 0.005), but the association was less strong compared with non-NHT patients (HR 2.9, P < 0.0001). Utilization of the Gleason system appears feasible among hormonally pretreated prostatectomy specimens and shows continued prognostication for systemic progression. Confirmatory investigations are needed before the Gleason system can be reliably applied in the setting of neoadjuvant therapy.

Androgen deprivation therapy improves pneumoperitoneum time during laparoscopic radical prostatectomy in Japanese patients with enlarged prostates

The aim of this study was to investigate if neoadjuvant hormone therapy (NHT) is associated with surgical outcomes of laparoscopic radical prostatectomy. A total of 286 patients with organ-confined prostate cancer and a preoperative prostate volume that could be estimated by transrectal ultrasound underwent laparoscopic radical prostatectomy between 2006 and 2011 at our institution. We examined whether NHT was associated with pneumoperitoneum time (PT) or estimated blood loss during laparoscopic radical prostatectomy. NHT was performed in 80 patients; the mean duration of NHT was 5.2 ± 0.2 months. Multivariate analysis demonstrated that history of NHT and no NHT were not independent predictors of prolonged PT or higher estimated blood loss. Next, we evaluated 57 patients whose estimated preoperative baseline prostate volume was over 50 mL. Multivariate analysis demonstrated that no history of NHT (P = 0.011) was an independent predictor of prolonged PT. PT was significantly shorter in the NHT group (164.5 ± 39.0 min, n = 26) than in the non-NHT group (184.0 ± 36.7 min, n = 31) (P = 0.048). In the NHT group, mean prostate volume was reduced from 63.7 ± 16.0 mL to 42.1 ± 18.6 mL (33.9% reduction) by NHT. NHT shortened the PT of the patients whose preoperative baseline prostate volume was over 50 mL. This suggests NHT downsized prostate volume, resulting in greater working space and shorter PT.

Risk factors of recurrence after radical prostatectomy for locally advanced prostate cancer

We reviewed our retrospective surgical database and assessed the outcome after radical prostatectomy (RP) in patients with clinical T3 (cT3) prostate cancer (PC). Sixty four men underwent RP for cT3 PC in our hospital from 1995 to 2011. Clinical stage was diagnosed with MRI and rectal digital examination in all cases. We investigated the postoperative outcome, cancer specific survival and overall survival of all patients. We also investigated the risk factors of biochemical recurrence (BCR) in the patients without any adjuvant therapy. All survival was estimated using Kaplan-Meier plots. We performed univariate analysis by Mann-Whitney test, Fisher exact test and Log-Rank test, and multivariate analysis by Cox regression analysis. Median age at RP was 67 years (range: 48-74), and median initial PSA was 14.1 ng/ml (2.2-76.2). Sixty cases (93.8%) were classified into cT3a, and 4 cases (6.3%) into cT3b. Median follow-up period after RP was 62 months (3-172). Fifty three (83%) patients received neoadjuvant hormonal therapy. Median duration of neoadjuvant hormonal therapy was 7 months (3-31). Adjuvant therapy underwent in 20 cases. Of the 64 patients, overall survival and cancer specific survival rates at 10 years were 98% and 100%, respectively. Of the 44 patients who didn't receive any adjuvant therapy, BCR free survival rates at 5 and 10 years was 59% and 51%, respectively. Univariate analysis revealed that both PSA > or = 15 ng/ml and GS > or = 8 were associated with a significant risk of BCR. Any significant risk factor was not identified by multivariate analysis. In 16 patients who have cT3a, PSA < 15 ng/ml and GS < 8, BCR free survival rate at 5 years was 78%. On the other hand, that of the other patients was 37% (p = 0.009). It is suggested that RP is effective for some patients with locally advanced prostate cancer, especially who have cT3a diagnosed by MRI, PSA < 15 ng/ml and GS < 8.

Impact of Sociodemographic Factors on Management of Breast Cancer: Results of QRRO Survey

neoadjuvant hormone therapy (NAHT) versus (vs) those treated with neoadjuvant chemotherapy (NACT) followed by surgery with or without radiation (XRT). Materials/Methods: We reviewed the records of 110 consecutive postmenopausal women treated pre-operatively with either NAHT or NACT from 2004 to 2011. We included subjects with non-metastatic, noninflammatory, ER+ breast cancer and excluded those with Her2neu positive tumors. We compared pathologic complete response (pCR) and breast conserving surgery (BCS) rates as well as long-term rates of local control, distant metastasis free survival (DMFS), and overall survival (OS). Results: Median follow-up time for all patients was 45.7 months. Twentyeight subjects received NAHT, while 82 received NACT. The most commonly prescribed NAHT was an aromatase inhibitor (93%) followed by tamoxifen (7%). Median duration of NAHT was 8.0 months. Fifty-six percent of NACT patients received an anthracycline (A) and taxane-based regimen, while 33% of patients received an A-based regimen alone. Patients receiving NAHT were older than patients receiving NACT (Median age 67 vs 58 years, p < 0.01). There were no significant differences in initial T stage, clinical tumor size, progesterone receptor status, tumor grade, or histology between groups. NACT patients, however, had more advanced N stage compared to NAHT patients (p Z .03). All NAHT patients had residual invasive cancer at the time of surgery, while 7.3% of NACT subjects achieved a pCR (p Z 0.1). Indeed, NACT patients were more likely to develop any pathologic response to treatment (median tumor size decrease of 1.7 cm vs 1.0 cm in NAHT patients, p Z .05), but were less likely to undergo BCS than NAHT subjects (30% vs 68%, p < 0.01). Among BCS patients, 96% of the NACT vs 79% of NAHT patients received post-lumpectomy XRT (p Z .09). Among patients treated with mastectomy, NACT patients were more likely to receive XRT (78% vs 43%, p Z .05). Among all patients, only one patient developed a local recurrence following NAHT and mastectomy without XRT. There was no difference in 4-year DMFS or OS between groups. On multivariate analysis, tumor grade and N stage but not NAHT predicted for poorer OS. Conclusions: Our data suggests that although pCR rates following NAHT in post-menopausal patients with ER+ breast cancer are low, outcomes do not appear to be adversely affected by NAHT treatment in our patient population. NAHT appears to be a viable and potentially less toxic option in select post-menopausal women with ER+ breast cancer. Author Disclosure: D.M. Marcus: None. R. Prabhu: None. R. O’Regan: None. A. Zelnak: None. C. Fasola: None. D. Mister: None. M. Torres: None.

Long-term outcomes of three-dimensional conformal radiation therapy combined with neoadjuvant hormonal therapy for Japanese patients with T1c-T2N0M0 prostate cancer

The outcomes of three-dimensional conformal radiation therapy (3D-CRT) combined with neoadjuvant hormonal therapy (NAHT) in Japanese patients with T1c-T2N0M0 prostate cancer, with initiation of salvage hormonal therapy (SHT) at a relatively early phase, were analyzed. Fifty-nine Japanese patients with T1c-T2N0M0 prostate cancer who received radical 3D-CRT between January 1999 and January 2003 were evaluated. The median age, initial prostate-specific antigen (PSA) level, and duration of NAHT were: 72 years, 9.4 ng/ml, and 6 months, respectively. Seventy Gy was given in 35 fractions confined to the prostate ± seminal vesicles. AHT was not administered after 3D-CRT in any patients. The median follow-up period was 89 months. The median PSA value at the time of initiation of SHT was 4.7 ng/ml (range 0.1-21.6 ng/ml). The overall, disease-specific, PSA failure-free (based on the Phoenix definition), and SHT-free survival rates at 8 years were 82.8% (95% confidence interval [CI] 72.4-93.2), 100%, 62.4% (47.1-77.8), and 82.6% (71.3-94.0), respectively. Only one patient developed grade 3 late toxicity. The PSA control rates in our series of Japanese patients with stage T1c-T2N0M0 prostate cancer treated with the standard dose of 3D-CRT combined with NAHT seemed at least comparable to those reported from Western countries; as well, the patients had excellent outcomes. The present outcomes can be used as basic data for evaluating the impact of dose escalation with intensity-modulated radiation therapy for Japanese patients with prostate cancer in the future.

Testosterone recovery after permanent prostate seed implantation in patients with neoadjuvant hormonal therapy.

e15067 Background: The PSA kinetics in patients undergoing prostate brachytherapy with neoadjuvant hormonal therapy (NHT) is dependent on the recovery of serum testosterone(T) levels. When NHT was done, determination of PSA nadir is sometimes very confusing because of variety pattern of testosterone recovery. In this study, we assessed the duration of testosterone recovery and its effect on PSA kinetics in Asian (Japanese) men. Methods: From March 2004 to September 2010, 612 patients underwent I125 seed implantation in our institution. The records of 306 patients with NHT and a minimum of 2 years of follow-up were reviewed. Among those, 243 had serum testosterone level measurement every 3-6 months. All patients had at least 2 years of follow-up and were ceased androgen ablation after seed implantation. Prognostic factors for testosterone recovery were examined using multivariate Cox regression analysis. Results: Of 243 patients (age 48-81) with T1-T2 N0M0 prostate cancer, 207 had appropriate data. NHT included maximum androgen blockade (MAB) in 47 patients (22.7%), LHRH analog (LHRHa) in 157 (75.8%) and anti-androgen agent in 3(1.5%). The median duration of NHT was 11 months (range 3-72M). 94.7% of patients (n=196) recovered normal T levels (7.2 nmol/l) and median time to recover was 6.9 months (MAB group 9.0M, LHRHa group 6.5M). When PSA nadir was defined after 6.9M (207 days) of brachytherapy, 2 patients (4.3%) had biochemical failure (BF; nadir+2ng/dl) and 2 (4.3%) had PSA bounce (PB) in MAB group while 3 patients (1.9%) had BF and 7 (4.5%) had PB in LHRHa group. Total BF free rate was 5.8% and PSA bounce rate was 16.0%. 11 patients (5.3%, median NHT duration 10 months) did not recover normal T levels. On multivariate analysis, younger age (p=0.016, 95% C.I. 0.945-0.994) and the use LHRHa as compared with MAB (p=0.004. 95% C.I. 0.028-0.504) could be the prognostic factors for testosterone recovery. The duration of NHT was not significant (p=0.211) in this study. Conclusions: 78.3% and 95.4% of patients recovered normal serum testosterone levels within a year and 2 years, respectively. Defining PSA nadir according to T recovery seems useful in appropriate follow-up of patients undergoing brachytherapy with NHT.

A comparison of preplan MRI and preplan CT-based prostate volume with intraoperative ultrasound-based prostate volume in real-time permanent brachytherapy

PurposeThe present study compared the difference between intraoperative transrectal ultrasound (iTRUS)-based prostate volume and preplan computed tomography (CT), preplan magnetic resonance imaging (MRI)-based prostate volume to estimate the number of seeds needed for appropriate dose coverage in permanent brachytherapy for prostate cancer.Materials and MethodsBetween March 2007 and March 2011, among 112 patients who underwent permanent brachytherapy with 125I, 60 image scans of 56 patients who underwent preplan CT (pCT) or preplan MRI (pMRI) within 2 months before brachytherapy were retrospectively reviewed. Twenty-four cases among 30 cases with pCT and 26 cases among 30 cases with pMRI received neoadjuvant hormone therapy (NHT). In 34 cases, NHT started after acquisition of preplan image. The median duration of NHT after preplan image acquisition was 17 and 21 days for cases with pCT and pMRI, respectively. The prostate volume calculated by different modalities was compared. And retrospective planning with iTRUS image was performed to estimate the number of 125I seed required to obtain recommended dose distribution according to prostate volume.ResultsThe mean difference in prostate volume was 9.05 mL between the pCT and iTRUS and 6.84 mL between the pMRI and iTRUS. The prostate volume was roughly overestimated by 1.36 times with pCT and by 1.33 times with pMRI. For 34 cases which received NHT after image acquisition, the prostate volume was roughly overestimated by 1.45 times with pCT and by 1.37 times with pMRI. A statistically significant difference was found between preplan image-based volume and iTRUS-based volume (p < 0.001). The median number of wasted seeds is approximately 13, when the pCT or pMRI volume was accepted without modification to assess the required number of seeds for brachytherapy.ConclusionpCT-based volume and pMRI-based volume tended to overestimate prostate volume in comparison to iTRUS-based volume. To reduce wasted seeds and cost of the brachytherapy, we should take the volume discrepancy into account when we estimate the number of 125I seeds for permanent brachytherapy.

Commentary on “Is biochemical response more important than duration of neoadjuvant hormone therapy before radiotherapy for clinically localized prostate cancer? An analysis of the 3- vs. 8-month randomized trial”. Alexander A, Crook J, Jones S, Malone S, Bowen J, Truong P, Pai H, Ludgate C, Radiation Therapy Program, British Columbia Cancer Agency, Vancouver Island Centre, University of British Columbia, Victoria,

Commentary on “Is biochemical response more important than duration of neoadjuvant hormone therapy before radiotherapy for clinically localized prostate cancer? An analysis of the 3- vs. 8-month randomized trial”. Alexander A, Crook J, Jones S, Malone S, Bowen J, Truong P, Pai H, Ludgate C, Radiation Therapy Program, British Columbia Cancer Agency, Vancouver Island Centre, University of British Columbia, Victoria,

Long-term outcomes of three-dimensional conformal radiation therapy combined with neoadjuvant hormonal therapy in Japanese patients with locally advanced prostate cancer

The outcomes of three-dimensional conformal radiation therapy (3D-CRT) combined with neoadjuvant hormonal therapy (NAHT) in Japanese patients with locally advanced prostate cancer who initiated salvage hormonal therapy (SHT) at a relatively early phase were evaluated. Between April 1998 and April 2003, 70 Japanese patients with T3N0M0 prostate cancer who received radical 3D-CRT treatment were evaluated. The median age, initial prostate-specific antigen (PSA) level, and duration of NAHT were 73 years old, 26.3 ng/ml, and 4 months, respectively. Seventy grays were given in 35 fractions that were confined to the prostate and seminal vesicles. Adjuvant hormonal therapy was not administered after 3D-CRT in any of the cases. The median follow-up period was 64.9 months. The median PSA value at the time of initiation of SHT was 5.0 ng/ml (range 0.1-21.6 ng/ml). Overall, disease-specific, PSA failure-free (based on the Phoenix definition) and SHT-free survival rates at 5 years were 90.3% (95% CI 86.5-94.0), 96.5% (94.0-98.9), 60.5% (48.2-72.7), and 63.5% (57.2-69.8), respectively. Therefore, two-thirds of the patients were still hormone-free at 5 years. PSA control rates in our series of Japanese patients with stage T3N0M0 prostate cancer treated with the standard dose of 3D-CRT combined with NAHT seemed higher than expected. This approach involving 3D-CRT combined with NAHT with the initiation of SHT at PSA values of around 5 ng/ml may be one option for Japanese patients with locally advanced prostate cancer, although further prospective study is required to confirm the validity.

Is Biochemical Response More Important Than Duration of Neoadjuvant Hormone Therapy Before Radiotherapy for Clinically Localized Prostate Cancer? An Analysis of the 3- Versus 8-Month Randomized Trial

To ascertain whether biochemical response to neoadjuvant androgen-deprivation therapy (ADT) before radiotherapy (RT), rather than duration, is the critical determinant of benefit in the multimodal treatment of localized prostate cancer, by comparing outcomes of subjects from the Canadian multicenter 3- vs 8-month trial with a pre-RT, post-hormone PSA (PRPH-PSA) < or =0.1 ng/ml vs those >0.1 ng/ml. From 1995 to 2001, 378 men with localized prostate cancer were randomized to 3 or 8 months of neoadjuvant ADT before RT. On univariate analysis, survival indices were compared between those with a PRPH-PSA < or =0.1 ng/ml vs >0.1 ng/ml, for all patients and subgroups, including treatment arm, risk group, and gleason Score. Multivariate analysis identified independent predictors of outcome. Biochemical disease-free survival (bDFS) was significantly higher for those with a PRPH-PSA < or =0.1 ng/ml compared with PRPH-PSA >0.1 ng/ml (55.3% vs 49.4%, p = 0.014). No difference in survival indices was observed between treatment arms. There was no difference in bDFS between patients in the 3- and 8-month arms with a PRPH-PSA < or =0.1 ng/ml nor those with PRPH-PSA >0.1 ng/ml. bDFS was significantly higher for high-risk patients with PRPH-PSA < or =0.1 ng/ml compared with PRPH-PSA >0.1 ng/ml (57.0% vs 29.4%, p = 0.017). Multivariate analysis identified PRPH-PSA (p = 0.041), Gleason score (p = 0.001), initial PSA (p = 0.025), and T-stage (p = 0.003), not ADT duration, as independent predictors of outcome. Biochemical response to neoadjuvant ADT before RT, not duration, appears to be the critical determinant of benefit in the setting of combined therapy. Individually tailored ADT duration based on PRPH-PSA would maximize therapeutic gain, while minimizing the duration of ADT and its related toxicities.

Biochemical Response is More Critical than Total Duration of Neo-adjuvant Hormone Therapy (NAHT) Prior to Radiotherapy for Localized Prostate Cancer: Analysis of the 3 vs 8 Month Data

Results: Mean patient age was 70 years, with 30.3%, 42.7%, and 26.9% harboring low, intermediate, and high-risk disease, respectively. OS, bDFS, and PCSS for the entire group was 81.5%, 52.3%, and 93.3%, respectively. For all patients, bDFS was significantly higher with a PHPR-PSA\0.1ng/mL (55.3% vs. 49.4%, p = 0.014). There were no significant differences in OS, bDFS, or PCSS between the 3- and 8-month arms. Within the 8-month arm, bDFS was significantly higher for those with a PHPR-PSA \0.1ng/mL compared to .0.1ng/mL (66.1% vs. 50.9%, p = 0.026). No differences were observed in survival indices between the 3- and 8-month arms for patients with a PHPR-PSA\0.1ng/mL, nor for those with a PHPR-PSA .0.1ng/mL. Patients with highrisk disease had significantly higher bDFS with a PHPR-PSA\0.1ng/mL (57.0% vs. 29.4%, p = 0.017). The same was true for patients with Gleason 8-10 (64.3% vs. 29.6%, p = 0.047). Patients with an initial PSA 10-20ng/mL and PSA .20ng/mL had a significantlyhigherbDFSwithaPHPR-PSA\0.1ng/mL(55.9%vs.34.3%,p=0.047;and54.6%vs.28.0%,p=0.047,respectively). On multivariate analysis only PHPR-PSA (HR 0.642, p = 0.044) and T-stage (HR 2.269, p = 0.026) were found to be independent predictors of bDFS. Duration of ADT was not significant (p .0.05). Conclusions:Thesefindings suggest that in the setting of NAHT prior to RT for prostate cancer, ADT should be continued at least until PSA falls below 0.1ng/mL before initiation of RT, rather than for a fixed duration. The biochemical benefit of NAHT given in this fashion is more pronounced in patients with higher risk disease features.

The Limited Significance of a Longer Duration of Neoadjuvant Hormonal Therapy prior to Radical Prostatectomy for High-Risk Prostate Cancer in Japanese Men

Introduction: The objective of this study was to evaluate the therapeutic significance of a longer duration of neoadjuvant hormonal therapy (NHT) followed by radical prostatectomy (RP) in Japanese men with high-risk prostate cancer. Materials and Methods: This study included a total of 42 patients with high-risk prostate cancer who were treated with NHT for ≧8 months prior to RP. In this series high-risk prostate cancer was defined as clinical stage T2c or T3, pretreatment serum prostate-specific antigen (PSA) >20 ng/ml and/or a biopsy Gleason score of 8–10. Biochemical recurrence was defined as a serum PSA level of ≧0.2 ng/ml. The data of these patients were retrospectively reviewed to clarify the relationships between treatment outcomes and various clinicopathological parameters. Results: The clinical stage was T2c in 13 patients and T3 in 29, the median value of pretreatment serum PSA was 43.3 ng/ml (range 9.7–322.2), and the biopsy Gleason score was 6 in 3 patients, 7 in 16 and ≧8 in 23. Following NHT (median 12 months, range 8–27), the median value of serum PSA decreased to 0.05 ng/ml (<0.01–18.3 ng/ml), and 15 patients (35.7%) were pathologically downstaged. During the median follow-up of 38 months (range 8–58), 11 patients (26.2%) developed biochemical recurrence, and the multivariate analysis identified pretreatment serum PSA, biopsy Gleason score and percentage of positive biopsy core as independent predictors of biochemical recurrence. The 3-year biochemical recurrence-free survival rate of the 42 patients was 68.3%, which was not significantly different from that of 34 patients who underwent RP for high-risk prostate cancer without NHT during the same period. Conclusion: A longer duration of NHT followed by RP for patients with high-risk prostate cancer resulted in a comparatively favorable outcome. However, despite the nonrandomized retrospective analysis, the present findings suggest no significant impact of long-term NHT on biochemical recurrence. Longer follow-up is needed to determine whether this therapeutic strategy is beneficial for high-risk prostate cancer patients.

Optimising Hormone Therapy in Localised and Early Disease

Prostate cancer (PCa) is being diagnosed at an earlier age, and at an earlier stage of disease. Increasing numbers of relatively young patients (<60 years) with localised and early disease are receiving radical therapy. The addition of hormonal therapy in an adjuvant and/or neoadjuvant setting is widely used in clinical practice. The key issue when dealing with optimising hormone therapy in localised and early disease is to identify the patients who will benefit from this form of treatment, and optimise the timing of initiation as well as duration of the treatment. The current literature was reviewed to address this issue. Traditionally, most patients diagnosed with localised disease receive radical therapy, either radiation therapy or radical prostatectomy. However, many men have indolent PCa and may not require radical therapy. In contrast, patients with aggressive disease benefit from local therapy. As a consequence, the main clinical challenge is the stratification of patients with localised disease into good risk patients and intermediate-to-high risk patients in order to offer the patient a tailored treatment strategy. Patients diagnosed with good risk disease (stage T1c–T2a, Gleason score ≤6, small volume of disease on biopsy and prostate specific antigen (PSA) ≤10 ng/mL) can be closely monitored with periodic biopsies and measurement of the PSA doubling time (DT). Patients diagnosed with an aggressive form of disease (intermediate-to-high risk disease) need immediate curative therapy. Both radical prostatectomy and radiotherapy are currently used in combination with neoadjuvant and/or adjuvant hormonal therapy. Neoadjuvant therapy prior to radical prostatectomy has failed to demonstrate an improvement in PSA progression in numerous randomised trials. However, one trial showed a benefit in high risk patients (PSA >20 ng/mL) after 3 months of neoadjuvant therapy, based on retrospective stratification analysis. Overall, some practitioners recommend neoadjuvant therapy for patients with high risk localised PCa. Adjuvant hormonal therapy after surgery has not, to date, demonstrated an improvement in overall or disease specific survival, but does delay PSA progression. The significance of this remains uncertain. Neoadjuvant hormonal therapy prior to radiation therapy is recommended for patients with intermediate-to-high risk disease. The optimal duration of neoadjuvant hormone therapy is not yet defined. However, a 3 to 6 month course of neoadjuvant therapy prior to radiation is widely utilised. Adjuvant hormonal therapy after radiotherapy is also widely used in patients with intermediate-to-high risk disease. The optimal duration of adjuvant therapy is between 6 months and 3 years. For patients with biochemical failure, androgen deprivation therapy is appropriate for those whose clinical and pathologic parameters indicate that local recurrence is unlikely. For such patients who are at high risk (Gleason ≥8, or PSA DT <1 year), androgen deprivation should be implemented when the PSA is between 5 and 10 ng/mL. For lower risk patients, or those who have secondary failure after initial attempt at salvage radiation, there is no evidence that early androgen deprivation enhances survival or time to androgen independent progression. These patients should be monitored and treated upon clinical progression or rapid biochemical progression.

Relationship between changes in prostate cancer cell proliferation, apoptotic index, and expression of apoptosis-related proteins by neoadjuvant hormonal therapy and duration of such treatment

Objectives To investigate the relationships between changes in the carcinoma cell proliferation index, apoptotic index (AI), and apoptosis-related factors, including bcl-2 and bax, after different durations of neoadjuvant hormonal therapy (NHT) in prostate cancer tissue. Methods Pre- and post-NHT specimens were obtained from 42 patients who had undergone NHT and radical prostatectomy. The patients were divided into two groups according to the duration of NHT: group 1 (3 to 7 months, n = 21) and group 2 (8 to 12 months, n = 21; no randomization). Immunohistochemistry was used to determine the expression of bcl-2 and bax and to determine the proliferation index, and the terminal deoxynucleotidyl transferase-mediated nick end-labeling method was used to assess apoptosis and determine the AI. Results The median proliferation indexes of groups 1 (1.8%) and 2 (1.6%) were significantly lower than the respective values in the pre-NHT specimens (4.9%, P <0.01). The median AI of group 1 (2.5%) was greater than in the pre-NHT specimens (1.4%). In addition, the post/pre-NHT AI ratio correlated significantly with the duration of NHT in group 1 ( r = 0.58, P <0.01), but not in group 2. Bax expression increased in a manner parallel to that of the AI. Conclusions NHT suppresses prostate cancer cell proliferation for 3 to 12 months. Although the AI was increased during 3 to 7 months of NHT, no significant difference was found between the pre-NHT levels and those after 8 to 12 months. Our results support the current belief that the optimal duration of NHT is longer than 3 months.

Neoadjuvant hormone therapy and external-beam radiation for localized high-risk prostate cancer: The importance of PSA nadir before radiation

To examine the impact of various patient, disease, and treatment characteristics on outcome in patients treated with neoadjuvant hormone therapy (NAHT) and external-beam radiation therapy (EBRT) for clinically localized, high-risk prostate adenocarcinoma (initial prostate-specific antigen [PSA] level >20, Gleason score 8-10 or Stage > or = T3). A retrospective chart review was conducted on 407 patients treated between 1991 and 2001 with NAHT and EBRT for high-risk prostate cancer. The effect of tumor (PSA level, Gleason score, and T stage) and treatment (NAHT duration, total-hormone duration, preradiation PSA) characteristics on rates of biochemical disease-free survival (bDFS), prostate cancer-specific survival, and overall survival were examined. Median follow-up time was 78 months (range: 5-140 months). Actuarial bDFS at 5 years was 52% (95% confidence interval [CI], 46% to 57%) for the entire group. On multivariate analysis, initial PSA level (p = 0.004), Gleason score (p = 0.005), and preradiation PSA level (p < 0.001) were predictive of bDFS, whereas age, T stage, duration of NAHT, and duration of total hormone therapy were not predictive of outcomes. Gleason score and preradiation PSA level were also predictive of prostate cancer-specific survival rates. Improved bDFS in patients with high-risk prostate cancer was associated with lower initial PSA level, lower Gleason score, and lower preradiation PSA level. The duration of NAHT did not have an impact on outcomes, but the preradiation PSA was an important predictor of bDFS in high-risk patients.

No residual tumor in a radical prostatectomy specimen after neoadjuvant hormonal therapy for localized prostate cancer

The role of neoadjuvant hormonal therapy (NHT) before radical prostatectomy for localized prostate cancer remains controversial because many argue that apparent downstaging results in difficulties with the pathological evaluation of the neoadjuvant treated prostatectomy specimen. Furthermore, the downstaging to pT0 (no residual tumor), as reported by several institutions, remains questionable and is not yet confirmed by clinical or experimental evidence. To examine this issue and to assess the influence of NHT on downstaging, we investigated the stage pT0 status in radical prostatectomy specimens after NHT. We retrospectively reviewed 31 patients with histologically confirmed clinical stage T1c, T2 or T3 prostate cancer. All patients had received NHT for a mean duration of 5.2 months (range 2-19). We compared the pretreatment parameters (PSA, clinical stage, biopsy Gleason grade, number of positive cores, total length of cancer on each sextant biopsy or duration of NHT) to the pathological findings in the specimen sectioned at 3-mm thick after NHT. Five (16%) of 31 patients had no residual cancer (pT0) after radical prostatectomy, 8 (26%) had organ-confined disease (stage pT2), 6 (19%) had specimen confined disease, 10 (33%) had non-specimen confined disease and only 2 (6%) had lymph node metastasis. The histologic changes, including glandular atrophy and cytoplasmic vacuolation were stronger in specimens with a long duration (4 or more months) of NHT than those of a short duration (3 or less months). Multiple logistic regression analysis showed that only a longer duration of NHT was an independent predictor of a stage pT0 status in radical prostatectomy specimens after NHT (p=0.04, Odds ratio; 1.92, 95% CI; 1.03-3.56). Downstaging to pT0 occurs after duration of NHT of longer than 3 months. Further investigation of the optimal duration of NHT for downstaging and for improving patients' survival should be accomplished in randomized trials.

RANDOMIZED COMPARATIVE STUDY OF 3 VERSUS 8-MONTH NEOADJUVANT HORMONAL THERAPY BEFORE RADICAL PROSTATECTOMY: BIOCHEMICAL AND PATHOLOGICAL EFFECTS

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 PERIOPERATIVE CHARGE EQUIVALENCE OF INTERSTITIAL BRACHYTHERAPY AND RADICAL PROSTATECTOMY WITH 1-YEAR FOLLOWUP

We compare the comprehensive 1-year charges in a consecutive group of patients undergoing radical prostatectomy and transperineal interstitial brachytherapy for clinically localized prostate cancer at a single urban institution. A total of 60 consecutive men with clinically localized prostate cancer (T1-T2, N0, M0) were treated during a 15-month period with radical prostatectomy or interstitial brachytherapy. Hospital and outpatient records were analyzed for each patient in regard to preoperative, operative and postoperative charges. Parameters included number of encounters, diagnostic and therapeutic interventions, hospitalization and operative charges, and followup visits, diagnostic tests and interventions for 1 year. All charge calculations were based arbitrarily on the 1996 Medicare fee schedule, factoring in the mandated global charge reimbursement period of 90 days for both procedures. Of the patients 38 underwent radical prostatectomy (prostatectomy group) and 22 underwent interstitial brachytherapy (brachytherapy group). The brachytherapy group was older with higher pretreatment serum prostate specific antigen and clinical stage disease, and more frequently received neoadjuvant hormonal therapy compared to the prostatectomy group. The 2 groups were similar in Gleason score and, when applicable, duration of neoadjuvant hormonal therapy. Preoperative charges were 15.3% lower for prostatectomy than for brachytherapy (not statistically significant). Conversely, operative charges for prostatectomy were 13.5% higher (p = 0.04). The major difference among preoperative, operative and postoperative charges was for those incurred postoperatively by the brachytherapy group, which were 56.0% higher than those for the prostatectomy group ($2,285.20 versus $1,007.20, p = 0.0004). Transperineal interstitial seed implantation is perceived by many as more cost-effective than radical prostatectomy for patients with clinically localized prostate cancer. We demonstrated that when such patients were followed for 1 year, the comprehensive charges for radical prostatectomy and interstitial brachytherapy were equivalent.