Use Of Neoadjuvant Androgen Deprivation Therapy Research Articles

Long-Term Outcomes of Whole Gland Salvage Cryotherapy for Locally Recurrent Prostate Cancer following Radiation Therapy: A Combined Analysis of Two Centers

Radiation refractory prostate cancer (RRPCa) is common and salvage cryotherapy for RRPCa is emerging as a viable local treatment option. However, there is a paucity of long-term data. The purpose of this study is to determine long-term outcomes following salvage cryotherapy for RRPca. Patients undergoing salvage cryotherapy for biopsy-proven, localized RRPCa from 1992 through 2004 were prospectively accrued at two centers. Preoperative characteristics, perioperative morbidity and postoperative data were reviewed from our database. The primary outcomes were overall survival (OS) and disease-specific survival (DSS). The secondary outcomes were freedom from castration-resistant prostate cancer (CRPC) and freedom from androgen deprivation therapy (ADT). A total of 268 patients were identified with a median followup of 10.3 years. A total of 223 complication events were recorded; of them, 168 were Clavien I-II events and 55 Clavien III events. At 10 years, 69% had freedom from ADT and 76% had freedom from CRPC. The 10-year DSS rate was 81%, and the 10-year OS rate was 77%. A pre-salvage prostate specific antigen level of >10 ng/ml was associated with an increased risk of developing CRPC and initiation of ADT but was not associated with DSS or OS. The use of neoadjuvant ADT was associated with improved OS and DSS but did not affect freedom from CRPC or adjuvant ADT. Salvage cryotherapy for RRPCa provides excellent long-term freedom from ADT, CRPC and DSS with acceptable morbidity. OS at 10 years was 77%. Prospective trials are required for validation.

Neoadjuvant Androgen Deprivation Therapy Prior to Radical Prostatectomy: Recent Trends in Utilization and Association with Postoperative Surgical Margin Status.

In this study, we sought to describe the contemporary trends in utilization of neoadjuvant androgen deprivation therapy (ADT). As a secondary endpoint, we assessed the community-level effect of neoadjuvant ADT on positive surgical margins after radical prostatectomy (RP). Using the National Cancer Database (2004-2014), we identified patients with clinically localized prostate cancer (PCa) [cT1-4N0M0] treated with RP. The estimated annual percentage change (EAPC) mixed linear regression methodology was used for temporal trend analysis of neoadjuvant ADT. Observed differences in baseline characteristics between patients treated with neoadjuvant ADT versus those who were not were then controlled for using an inverse probability of treatment weighting (IPTW) approach. IPTW-adjusted analyses were then performed to examine the odds of positive surgical margins. Overall, 8184 (2.12%) and 377,843 (97.88%) individuals with PCa were treated with neoadjuvant ADT prior to RP versus RP only, respectively. There was a consistent trend in decreasing use of neoadjuvant ADT over time, with a nadir observed in 2011 [EAPC - 8.08; 95% confidence interval (CI) - 11.7 to - 4.32; p<0.05]. In IPTW-adjusted analyses, the odds of positive surgical margins were lower in patients receiving neoadjuvant ADT with low-risk [odds ratio (OR) 0.65; 95% CI 0.51-0.84; p<0.001] and intermediate-risk [OR 0.76; 95% CI 0.69-0.85; p<0.001] PCa. After a period of steady decline, there appears to be a modest trend towards increased utilization of neoadjuvant ADT in more recent years. We found an association between neoadjuvant ADT and decreased odds of positive surgical margins among low- and intermediate-risk patients.

Perioperative Search for Circulating Tumor Cells in Patients Undergoing Prostate Brachytherapy for Clinically Nonmetastatic Prostate Cancer.

Despite the absence of local prostate cancer recurrence, some patients develop distant metastases after prostate brachytherapy. We evaluate whether prostate brachytherapy procedures have a potential risk for hematogenous spillage of prostate cancer cells. Fifty-nine patients who were undergoing high-dose-rate (HDR) or low-dose-rate (LDR) brachytherapy participated in this prospective study. Thirty patients with high-risk or locally advanced cancer were treated with HDR brachytherapy after neoadjuvant androgen deprivation therapy (ADT). Twenty-nine patients with clinically localized cancer were treated with LDR brachytherapy without neoadjuvant ADT. Samples of peripheral blood were drawn in the operating room before insertion of needles (preoperative) and again immediately after the surgical manipulation (intraoperative). Blood samples of 7.5 mL were analyzed for circulating tumor cells (CTCs) using the CellSearch System. While no preoperative samples showed CTCs (0%), they were detected in intraoperative samples in 7 of the 59 patients (11.8%; preoperative vs. intraoperative, p = 0.012). Positive CTC status did not correlate with perioperative variables, including prostate-specific antigen (PSA) at diagnosis, use of neoadjuvant ADT, type of brachytherapy, Gleason score, and biopsy positive core rate. We detected CTCs from samples immediately after the surgical manipulation. Further study is needed to evaluate whether those CTCs actually can survive and proliferate at distant sites.

Statin use not associated with improved outcomes in patients treated with brachytherapy for prostate cancer.

To investigate the association between statin use and prostate cancer outcomes in intermediate- and high-risk patients treated with brachytherapy for prostate cancer. Between 1998 and 2010, 754 men with National Comprehensive Cancer Network intermediate- (n = 627) and high-risk (n = 127) prostate cancer were treated with prostate brachytherapy at our institution. Patients received either low-dose-rate or high-dose-rate brachytherapy as monotherapy or in combination with supplemental external beam radiotherapy. Two hundred eighty-five patients (37.8%) also received androgen-deprivation therapy. Two hundred seventy-three men (36.2%) were identified as taking statin medication before initiating radiation therapy. Prostate-specific antigen relapse-free survival (PSA-RFS), distant metastasis-free survival (DMFS), and overall survival were compared using log-rank tests. Associations of patient and treatment characteristics with outcomes were analyzed with univariate and multivariate regression. The median followup was 48 months. The 8-year PSA-RFS for intermediate-risk, high-risk, and all patients was 92.2%, 64.1%, and 87.7%, respectively. The 8-year DMFS was 97.1%, 82.9%, and 94.9%, respectively. The 8-year overall survival for the entire cohort was 86.6%. There were no significant differences between statin users and nonusers when stratified by risk group, nor when analyzed as a full cohort. On multivariate analysis, Gleason score 4 + 3 = 7 and >7 were significantly associated with worse PSA-RFS (p ≤ 0.003 and <0.001, respectively). Gleason score > 7 (p = 0.008) and the use of neoadjuvant androgen-deprivation therapy (p = 0.03) was associated with worse DMFS. Statin use did not significantly impact PSA-RFS or DMFS. Pretreatment statin use is not associated with improved outcomes in intermediate- and high-risk patients undergoing prostate brachytherapy-based regimens for prostate cancer.

Does Neoadjuvant Androgen Deprivation Therapy Before Primary Whole Gland Cryoablation of the Prostate Affect the Outcome?

To evaluate the effect of neoadjuvant androgen deprivation therapy (NADT) on the outcomes for primary whole gland prostate cryoablation (CRYO). NADT before CRYO has sometimes been used for prostate volume reduction, with some theoretical benefit toward improving disease control. NADT has been shown to be beneficial for biochemical disease-free survival (bDFS) with radiotherapy but not in conjunction with radical prostatectomy. We retrospectively compared risk-stratified cohorts according to whether they had received NADT. bDFS was defined using the Phoenix criteria, and postoperative morbidity and complications were compared. A total of 1761 men had undergone NADT before CRYO and 2727 had not. No differences were found in the incidence of postoperative incontinence, pad use, potency, or fistula formation. The rate of urinary retention at 12 months was slightly lower for those who had not undergone NADT (0.8% vs 1.2%, P = .015). No difference was found in bDFS between the NADT and non-NADT men (66.9% vs 66.5% at 5 years). When stratified by risk, however, a statistically significant difference was found between the NADT and non-NADT men only in the intermediate-risk cohort (71.3% vs 65.9%; P < .013). bDFS was statistically similar between the NADT and non-NADT men, except in the intermediate-risk cohort, with slightly improved survival for those undergoing NADT. No significant difference was found in the complication rates. These data do not support the routine use of NADT for men undergoing primary whole gland cryoablation, although its use could be considered for men with larger prostates or men in the intermediate-risk category.

345 CONTEMPORARY NATIONALLY-REPRESENTATIVE TRENDS IN TREATMENT FOR LOCALIZED PROSTATE CANCER

INTRODUCTION AND OBJECTIVES: Primary treatment trends for localized prostate cancer, including substantial local variation, have previously been documented among selected community-based U.S. practices. We aimed to determine whether these trends are confirmed in larger, more broadly representative databases. METHODS: We analyzed treatments in two national administrative datasets including men covered by Medicare in 1998–2006 and by private insurance (i3 database) in 2002–2006. Treatment distributions were determined in each year among watchful waiting/active surveillance (WW), radical prostatectomy (RP), radiation therapy (RT), cryotherapy, and primary androgen deprivation therapy (PADT). Trends in specific modalities were further examined within RP and RT. County-level variation was assessed, and treatment predictors were determined using multinomial regression. RESULTS: Among 54,322 Medicare patients (mean age at diagnosis 75), WW use fell from 30% in 1998 to 22% in 2002 and remained low. PADT use peaked at 24% in 2002 and fell to 17% by 2006. RP use varied between 11% and 13% during the study period, while RT use rose from 35 to 44%. Laparoscopic/robot-assisted RP (LRRP) and intensity-modulated radiation therapy (IMRT) were both first reported in 1999, and rose to 35% of RP and 53% of RT cases, respectively, by 2006. Among 16,161 privately insured patients (mean age 65), WW and PADT fell steadily from 25% and 12% in 2002, respectively, to 12% and 7% in 2006. RT use varied between 30 and 32%, while RP use rose from 33 to 48%. LRRP and IMRT use rose from 1% and 15% of RP and RT cases, respectively, in 2002 to 41% and 48% in 2006. Use of neoadjuvant androgen deprivation therapy (NADT) declined among RP and brachytherapy patients, to 6 and 25%, respectively, among Medicare patients and to 2% and 22% among private insurance patients by 2006. Use of NADT rose to 41% and fell to 37% among external-beam RT patients with Medicare and private insurance, respectively. There was considerable geographic variation in treatment selection. Across counties, use of WW, PADT, RP, and RT ranged, respectively, from 3 to 55%, 0 to 48%, 0 to 50%, and 15 to 71%. Comorbidity, age, income, year of diagnosis, and county-level sociodemographic variables predicted treatment. CONCLUSIONS: These trends echo those documented in prior studies in smaller datasets, and these data confirm extensive geographic variation. In both databases, there is rapid, ongoing adoption of high-cost technologies among both RP and RT patients. These findings underscore the urgent need for high-quality cost-effectiveness research comparing these treatments.

Extreme-Risk Prostate Adenocarcinoma Presenting With Prostate-Specific Antigen (PSA) >40 ng/ml: Prognostic Significance of the Preradiation PSA Nadir

To examine the impact of patient, disease, and treatment characteristics on survival outcomes in patients treated with neoadjuvant androgen deprivation therapy (ADT) and radical external-beam radiotherapy (RT) for clinically localized, extreme-risk prostate adenocarcinoma with a presenting prostate-specific antigen (PSA) concentration of >40 ng/ml. A retrospective chart review was conducted of 64 patients treated at a single institution between 1991 and 2000 with ADT and RT for prostate cancer with a presenting PSA level of >40 ng/ml. The effects of patient age, tumor (presenting PSA level, Gleason score, and T stage), and treatment (total ADT duration and pre-RT PSA level) characteristics on rates of biochemical disease-free survival (bDFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were examined. Median follow-up time was 6.45 years (range, 0.09-15.19 years). Actuarial bDFS, PCSS, and OS rates at 5 years were 39%, 87%, and 78%, respectively, and 17%, 64%, and 45%, respectively, at 10 years. On multivariate analysis, the pre-RT PSA level (≤0.1 versus >0.1 ng/ml) was the single most significant prognostic factor for bDFS (p=0.033) and OS (p=0.018) rates, whereas age, T stage, Gleason score, and ADT duration (≤6 versus >6 months) were not predictive of outcomes. In prostate cancer patients with high presenting PSA levels, >40 ng/ml, treated with combined modality, neoadjuvant ADT, and RT, the pre-RT PSA nadir, rather than ADT duration, was significantly associated with improved survival. This observation supports the use of neoadjuvant ADT to drive PSA levels to below 0.1 ng/ml before initiation of RT, to optimize outcomes for patients with extreme-risk disease.

Efficacy of Short-Term Androgen Deprivation With High-Intensity Focused Ultrasound in the Treatment of Prostate Cancer in Japan

To determine whether combining short-term neoadjuvant androgen deprivation therapy (NADT) with high-intensity focused ultrasound (HIFU) had a significant benefit in a large population of men with nonmetastatic prostate cancer (CaP). We evaluated the records of 530 patients whose prostate-specific antigen (PSA) level at diagnosis was 30 ng/mL or less and whose follow-up period was not less than 12 months, at seven investigational sites. Two hundred seventy patients had received NADT (within 6 months), and 260 had not. The primary outcome measure was disease-free survival according to the combined criteria satisfying the Phoenix definition (less than nadir + 2), negative prostate biopsy, and no findings of distant metastasis after the last HIFU treatment. The significance of the differences of values or the distributions of each parameter between two groups was evaluated with a Mann-Whitney U test, unpaired t test, or chi-square test, and a multivariate Cox proportional hazards model was used to evaluate the prognostic relevance of preoperative parameters. Statistical analyses showed that the NADT group had worse disease (higher PSA and risk group) than the HIFU-only group. Variables shown by multivariate analyses to be significant prognostic parameters were pretreatment PSA level, clinical stage, and no use of NADT. Short-term NADT significantly improved the 3-year disease-free survival rate of patients with intermediate-risk and high-risk CaP. During follow-up the frequencies of complications did not differ significantly with or without NADT. Our retrospective study suggests that combining short-term NADT with HIFU treatment is of significant clinical benefit to intermediate-risk and high-risk CaP patients without increasing the likelihood of complications.

Dose Escalated External Beam Radiotherapy versus Neoadjuvant Androgen Deprivation Therapy and Conventional Dose External Beam Radiotherapy for Clinically Localized Prostate Cancer: Do we Need Both?

Several randomized trials have demonstrated that men with localized prostate cancer benefit from the use of short-term neoadjuvant androgen deprivation therapy (NADT) in combination with external beam radiotherapy (EBRT), while other trials have shown improved outcomes with higher doses of radiation. This review compares both approaches and the rationale for using both. To date 4 randomized trials, including 10 arms and approximately 1600 men have reported comparing patients treated with EBRT alone to EBRT combined with short-term NADT. To date, four Phase III dose escalation trials have been completed including 8 arms and a total of approximately 2210 patients with doses up to 74 to 79 Gy compared to doses of 64 to 70 Gy on the control arms. All studies (n = 4) using NADT demonstrated an improvement in biochemical failure compared to patients treated with EBRT alone, three studies showed an improvement in cause specific survival and one showed an overall survival advantage, one showed a reduction in distant metastasis or the need for salvage ADT. All phase III dose escalation studies to date only show an improvement in biochemical control. The quality of the evidence supporting the use of NADT in combination with EBRT for clinically important endpoints is stronger than the data supporting dose escalation. Cure rates appear to be unacceptably low for both approaches such that higher doses of EBRT combined with NADT and whole pelvic radiotherapy may be indicated for optimal outcomes.

Histopathologic effects of three-dimensional conformal external beam radiation therapy on benign and malignant prostate tissues.

We reviewed 137 prostate sextant needle biopsies from 137 patients obtained at a median of 35.7 months after three-dimensional conformal external beam radiation therapy (3DCRT). Thirty-one patients (23%) received 3 months of androgen deprivation therapy (ADT) before 3DCRT. We also retrospectively reviewed and assigned a combined Gleason score to the pre-3DCRT needle biopsies (97 patients) or transurethral resection of the prostate gland (1 patient). High-molecular-weight cytokeratin (34betaE12) and prostate-specific antigen (PSA) immunohistochemistry was performed in select cases. After 3DCRT, histopathologic changes in benign prostate gland consisted of glandular atrophy, cytologic atypia, and basal cell prominence. The benign glands showed intensely positive reactions with antibodies to high-molecular-weight cytokeratin (34betaE12) and negative to weakly positive reactions to PSA. Paneth cell-like change was seen in 44 (32%) of the biopsies, mucinous metaplasia in 29 (21%), luminal blue-tinged mucinous secretions in 14 (10%), and squamous metaplasia in 8 (6%). The changes in benign prostate tissues were similar between patients treated with ADT and 3DCRT and those treated with 3DCRT alone. After 3DCRT, we recognized two histologic patterns of prostate cancer: (1) prostate cancer showing radiation therapy (RT)-related changes characterized by PSA-positive/34betaE12-negative poorly formed glands or individual cells with abundant clear to finely granular cytoplasm, and (2) prostate cancer showing no apparent RT effect. High-grade prostatic intraepithelial neoplasia (PIN) was seen in 12 post-3DCRT biopsies (8.8%). The use of neoadjuvant ADT had a significant impact on the results of post-RT biopsy. Of the 31 patients treated with neoadjuvant ADT and 3DCRT, 3 (10%) had post-3DCRT biopsies showing prostate cancer without RT effect compared to 44 of 106 men (41%) treated with 3DCRT alone (p = 0.004). Compared to the Gleason score pre-RT, the Gleason score of cancers showing no RT effect was the same in 25 patients (71%), +/-1 point in 8 patients (23%), and +2 points in 2 patients (6%). The mean combined Gleason score post-RT was slightly, although significantly, higher than that pre-RT (7.29 +/- 0.71 versus 7.00 +/- 0.59, p = 0.01). Serum PSA at the time of post-3DCRT biopsy correlated with biopsy results. Prostate cancer without therapy effect was seen in only one of 43 patients (2%) with a serum PSA level < or = 1 ng/ml compared to 46 of 94 patients (49%) with a PSA level > 1 ng/ml (p = 0.0001). After 3DCRT, benign prostate glands show profound histopathologic changes and may be confused with prostate cancer. The effects of 3DCRT on prostate cancer are variable, with some cases showing profound therapy-related changes and others showing no apparent therapy effect.

Evaluating neoadjuvant therapy effectiveness on systemic disease: Use of a prostatic-specific membrane reverse transcription polymerase chain reaction

Objective An on-going study at the Memorial Sloan-Kettering Cancer Center assessed the effectiveness of androgen deprivation therapy (ADT) prior to surgical removal of the prostate. In this report, we evaluate the effectiveness of ADT on systemic disease by monitoring the presence or absence of circulating prostatic epithelial cells using a reverse transcription polymerase chain reaction (RT-PCR) assay for prostatic-specific membrane antigen (PSM). Methods PSM RT-PCR was performed on a total of 38 prostate cancer patients. There were 12 pT2 patients in the ADT group and 10 patients in the control pT2 group and 5 pT3 patients in the ADT group and 11 pT3 patients in the control group. Results For pT2 patients, 2 of the 12 patients (17%) were positive for circulating prostatic cells during androgen deprivation therapy but before radical retroprostatectomy (RRP). Within a 6-month period after RRP, 3 of 12 patients (25%) were positive. For the period between the 7th and 12th month after RRP, 6 of 12 patients (50%) were positive. For the period 12–36 months after RRP, 2 of the 12 patients (17%) remained positive for circulating prostatic cells. In contrast, the pT2 control group had higher positive rates in comparable periods: 4 of 10 patients (40%) were positive prior to surgery; 6 of 10 patients (60%) were positive during the 6 months following surgery. For the period between the 7th and 12th month following surgery, 4 of 7 patients (57%) were positive for PSM. Finally, 3 of 6 patients (50%) were positive for the period longer than 12 months. Regarding patients who have extraprostatic disease (stage pT3), the ADT group had a lower rate of circulating PSM positive cells. Before RRP and during androgen deprivation therapy, 1 out of 5 patients (20%) in the ADT group were positive as compared to 4 out of 11 patients for the control group. Within a 6-month period after RRP, the ADT group had 4 out of 9 (44%) patients positive for PSM as compared to 9 of 11 (82%) for the control group. For the period between the 7th and 12th months postsurgery, 1 of 5 patients (20%) of the ADT group were positive as compared to 4 of 7 (57%) of the control patients. Conclusions These results indicate that patients with pT2 and pT3 lesions who receive neoadjuvant ADT are less likely to have circulating tumor cells detected compared to a control group both prior to and after surgery. In addition, irrespective of ADT or control group, there were increases in the detection of circulating tumor cells in the period after RRP, and this rise gradually decreased, suggesting that surgical manipulation may cause hematogenous dissemination of tumor cells and that ADT reduces such dissemination of tumor cells. Overall, these results indicate that the use of neoadjuvant ADT decreases the number of circulating prostatic cells. These data represent the initial results of an on-going study. As additional patients are added to the studies, attempts to correlate PSM positivity and serum PSA values postoperatively, recurrence, and margin positivity will be made.