Total Androgen Suppression Research Articles

Dose-Escalated Radiation Alone or in Combination With Short-Term Total Androgen Suppression for Intermediate-Risk Prostate Cancer: Patient-Reported Outcomes From NRG/Radiation Therapy Oncology Group 0815 Randomized Trial.

To report patient-reported outcomes (PROs) of a phase III trial evaluating total androgen suppression (TAS) combined with dose-escalated radiation therapy (RT) for patients with intermediate-risk prostate cancer. Patients with intermediate-risk prostate cancer were randomly assigned to dose-escalated RT alone (arm 1) or RT plus TAS (arm 2) consisting of luteinizing hormone-releasing hormone agonist/antagonist with oral antiandrogen for 6 months. The primary PRO was the validated Expanded Prostate Cancer Index Composite (EPIC-50). Secondary PROs included Patient-Reported Outcome Measurement Information System (PROMIS)-fatigue and EuroQOL five-dimensions scale questionnaire (EQ-5D). PRO change scores, calculated for each patient as the follow-up score minus baseline score (at the end of RT and at 6, 12, and 60 months), were compared between treatment arms using a two-sample t test. An effect size of 0.50 standard deviation was considered clinically meaningful. For the primary PRO instrument (EPIC), the completion rates were ≥86% through the first year of follow-up and 70%-75% at 5 years. For the EPIC hormonal and sexual domains, there were clinically meaningful (P < .0001) deficits in the RT + TAS arm. However, there were no clinically meaningful differences by 1 year between arms. There were also no clinically meaningful differences at any time points between arms for PROMIS-fatigue, EQ-5D, and EPIC bowel/urinary scores. Compared with dose-escalated RT alone, adding TAS demonstrated clinically meaningful declines only in EPIC hormonal and sexual domains. However, even these PRO differences were transient, and there were no clinically meaningful differences between arms by 1 year.

Dose Escalated Radiotherapy Alone or in Combination With Short-Term Androgen Suppression for Intermediate Risk Prostate Cancer: Outcomes From the NRG Oncology/RTOG 0815 Randomized Trial

Dose Escalated Radiotherapy Alone or in Combination With Short-Term Androgen Suppression for Intermediate Risk Prostate Cancer: Outcomes From the NRG Oncology/RTOG 0815 Randomized Trial

Dose Escalated Radiotherapy (RT) Alone or in Combination With Short-Term Total Androgen Suppression (TAS) for Intermediate Risk Prostate Cancer: Patient Reported Outcomes (PROs) From the NRG Oncology/RTOG 0815 Randomized Trial

<h3>Purpose/Objective(s)</h3> To report the PROs of a phase III randomized trial evaluating TAS combined with dose-escalated RT for patients with intermediate risk prostate cancer. <h3>Materials/Methods</h3> Eligible patients had intermediate risk prostate cancer defined as harboring ≥ 1 of these risk factors: clinical stage T2b-T2c, Gleason score 7, or PSA > 10 to ≤ 20 ng/mL. Patients were randomized to dose-escalated RT alone (Arm 1) or RT plus TAS (Arm 2) consisting of LHRH agonist/antagonist with oral antiandrogen for 6 months. Validated PROs included the Expanded Prostate Cancer Index Composite (EPIC-50) and Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue short form. PRO change scores, calculated for each patient as the follow-up score minus baseline score (at end of RT, 6, 12, and 60 months from start of RT) were compared between treatment arms using a two-sample <i>t</i> test. An effect size (ES) of 0.50 SD (standard deviation) of the baseline measure was considered clinically meaningful. For the PRO sample size, 200 patients per arm would provide 90% statistical power to detect an ES < 0.50 if the completion rate was only 60%. Mixed effect regression models were also utilized. Clinical outcomes are reported in a separate abstract. <h3>Results</h3> Of the 402 initial planned subset of trial patients who completed baseline PROs, PRO compliance was approximately 96%, 89%, 86% and 87% at end of RT, 6, 12 and 60 months, respectively. There were no significant differences between these 402 patients and the remaining patients on this trial with respect to age, race, performance status, # risk factors, or comorbidity score. While EPIC urinary and bowel scores decreased significantly by the end of RT in both arms, no clinically meaningful differences between arms were detected over time. For the EPIC hormonal and sexual domains, however, there were clinically meaningful differences between the two arms with greater (<i>P</i> < 0.0001) deficits in the RT + TAS arm. These differences improved over time, with ∼50% resolution by one year after treatment and no clinically meaningful differences by 5 years between arms. PROMIS-fatigue scores increased from baseline in both arms and were significantly higher in arm 2 at the end of RT (<i>P</i> = 0.016), though slightly lower at 12 and 60 months. <h3>Conclusion</h3> The addition of TAS to dose-escalated RT demonstrated significant clinically meaningful declines in the EPIC hormonal and sexual domains, and increases in the PROMIS-fatigue scores, compared to RT alone. These scores gradually improved over time, with no clinically meaningful differences between arms in fatigue by one year, or in hormonal and sexual domains by 5 years. Beyond the clinical outcomes, these PRO results directly from patients provide added value to help patients make informed decisions among treatment options.

Targeting Metastatic Hormone Sensitive Prostate Cancer: Chemohormonal Therapy and New Combinatorial Approaches.

Androgen deprivation therapy alone has been the standard of care for metastatic hormone sensitive prostate cancer for the last 75 years. This review focuses on recent trials and mechanisms which highlight the new paradigm of combining androgen deprivation therapy with other agents, changing the treatment of patients with prostate cancer who have advanced disease. We searched the peer reviewed literature on the PubMed® and Web of Science® databases through January 2018 using the key words, "metastatic hormone sensitive prostate cancer," "metastatic castration sensitive prostate cancer," "docetaxel," "abiraterone" and "senescence in cancer." ClinicalTrials.gov was queried for ongoing studies. Relevant data recently presented at major urology and medical oncology meetings were also evaluated. Recently published, phase III trials using androgen deprivation therapy combinations for metastatic hormone sensitive prostate cancer can be broadly grouped into chemohormonal studies (docetaxel) or trials of androgen signaling inhibitors. The CHAARTED (Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) studies showed a survival advantage when combining androgen deprivation therapy with chemotherapy, as well as increased time to progression to castration resistant status. The abiraterone arm of the STAMPEDE and LATITUDE trials, which analyzed combining androgen deprivation therapy with abiraterone, revealed improved overall and progression-free survival. Androgen deprivation therapy generates a number of phenotypes in resistant cancer cells, including quiescence, autophagy and cellular senescence. Senescent cells represent a metabolic target for synergistic lethality with drugs such as metformin. Ongoing trials are under way to examine the effect of combining newer antiandrogens and novel drugs with androgen deprivation therapy in patients with metastatic hormone sensitive prostate cancer. Combination therapy has evolved as the standard of care for metastatic hormone sensitive prostate cancer. The ideal combination is tailored to patients after individualized counseling taking into account general health and comorbid illness status.

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.

Importance of Local Control in Early-Stage Prostate Cancer: Outcomes of Patients With Positive Post-Radiation Therapy Biopsy Results Treated in RTOG 9408

The purpose of this study was to assess the association between positive post-radiation therapy (RT) biopsy results and subsequent clinical outcomes in males with localized prostate cancer. Radiation Therapy Oncology Group study 94-08 analyzed 1979 males with prostate cancer, stage T1b-T2b and prostate-specific antigen concentrations of ≤ 20 ng/dL, to investigate whether 4 months of total androgen suppression (TAS) added to RT improved survival compared to RT alone. Patients randomized to receive TAS received flutamide with luteinizing hormone releasing hormone (LHRH) agonist. According to protocol, patients without evidence of clinical recurrence or initiation of additional endocrine therapy underwent repeat prostate biopsy 2 years after RT completion. Statistical analysis was performed to evaluate the impact of positive post-RT biopsy results on clinical outcomes. A total of 831 patients underwent post-RT biopsy, 398 were treated with RT alone and 433 with RT plus TAS. Patients with positive post-RT biopsy results had higher rates of biochemical failure (hazard ratio [HR] = 1.7; 95% confidence interval [CI] = 1.3-2.1) and distant metastasis (HR = 2.4; 95% CI = 1.3-4.4) and inferior disease-specific survival (HR = 3.8; 95% CI = 1.9-7.5). Positive biopsy results remained predictive of such outcomes after correction for potential confounders such as Gleason score, tumor stage, and TAS administration. Prior TAS therapy did not prevent elevated risk of adverse outcome in the setting of post-RT positive biopsy results. Patients with Gleason score ≥ 7 with a positive biopsy result additionally had inferior overall survival compared to those with a negative biopsy result (HR = 1.56; 95% CI = 1.04-2.35). Positive post-RT biopsy is associated with increased rates of distant metastases and inferior disease-specific survival in patients treated with definitive RT and was associated with inferior overall survival in patients with high-grade tumors.

Radiation Therapy Oncology Group 9910: Phase 3 Trial to Evaluate the Duration of Neoadjuvant (NEO) Total Androgen Suppression (TAS) and Radiation Therapy (RT) in Intermediate-Risk Prostate Cancer (PCa)

Radiation Therapy Oncology Group 9910: Phase 3 Trial to Evaluate the Duration of Neoadjuvant (NEO) Total Androgen Suppression (TAS) and Radiation Therapy (RT) in Intermediate-Risk Prostate Cancer (PCa) T.M. Pisansky, D. Hunt, L.G. Gomella, M.B. Amin, A.G. Balogh, D.M. Chinn, M. Seider, M. Duclos, S.A. Rosenthal, and H.M. Sandler; Mayo Clinic, Rochester, MN, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA, Thomas Jefferson University, Philadelphia, PA, Cedars-Sinai Medical Center, Los Angeles, CA, Tom Baker Cancer Centre, Calgary, AB, Canada, John Muir Medical Center Concord Campus, Concord, CA, Akron City Hospital, Akron, OH, McGill University, Montreal, QC, Canada, Radiological Associates of Sacramento, Sacramento, CA

The biochemical efficacy of primary cryoablation combined with prolonged total androgen suppression compared with radiotherapy on high-risk prostate cancer: a 3-year pilot study

To gain beneficial effects in the management of high-risk prostate cancer, an integrated approach that combines local therapy and androgen deprivation therapy (ADT) was used. We compared biochemical responses between primary cryosurgical ablation of the prostate (CSAP) combined with prolonged ADT and radiation combined with ADT, which is the established modality in high-risk disease. A total of 33 high-risk patients received CSAP combined with ADT for 3 months before and up to 24 months after treatment. This patient group was matched with another 33 patients who had undergone three-dimensional conformal radiation therapy (3D-CRT) with the same protocol for ADT. Biochemical recurrence (BCR) was assessed by the American Society for Therapeutic Radiation Oncology (ASTRO) definition, the Phoenix definition and a prostate-specific antigen (PSA) cutoff of 0.5 ng mL(-1). Median follow-up was 61.0 ± 11.9 months for the CSAP + ADT group and 86.0 ± 15.8 months for the 3D-CRT + ADT group. In the CSAP group, major complications including rectourethral fistula and incontinence were not noted. In the CSAP + ADT group, 57.0% had BCR using the ASTRO definition, 21.2% using the Phoenix definition and 54.5% using a PSA cutoff of 0.5 ng mL(-1). In the 3D-CRT + ADT group, 54.5%, 21.2% and 54.5% had BCR using the ASTRO, Phoenix and PSA definition, respectively. In the CSAP + ADT group, the BCR-free survival (BRFS) was 54 ± 10 months using the ASTRO definition, 65 ± 5 months using the Phoenix definition and 51 ± 4 months using a PSA cutoff of 0.5 ng mL(-1). In the 3D-CRT + ADT group, the BRFS was 68 ± 12, 93 ± 19 and 70 ± 18 months using the ASTRO, Phoenix and PSA definition, respectively. By the log-rank test, the BRFS values for each group were not statistically different. This intermediate-term result indicated that primary CSAP combined with prolonged ADT offers a parallel biochemical response compared with radiotherapy in high-risk prostate cancer.

An update of the Phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: Updated analysis of RTOG 94-13 with emphasis on unexpected hormone/radiation interactions: Lawton CA, DeSilvio M, Roach M III, Uhl V, Kirsch R, Seider M, Rotman M, Jones C, Asbell S, Valicenti R, Hahn S, Thomas CR Jr., Department of

This trial was designed to test the hypothesis that total androgen suppression and whole pelvic radiotherapy (WPRT) followed by a prostate boost improves progression-free survival (PFS) by ≥10% compared with total androgen suppression and prostate only RT (PORT). This trial was also designed to test the hypothesis that neoadjuvant hormonal therapy (NHT) followed by concurrent total androgen suppression and RT improves PFS compared with RT followed by adjuvant hormonal therapy (AHT) by ≥10%. Patients eligible for the study included those with clinically localized adenocarcinoma of the prostate and an elevated prostate-specific antigen level <100 ng/ml. Patients were stratified by T stage, prostate-specific antigen level, and Gleason score, and were required to have an estimated risk of lymph node involvement >15%. The difference in overall survival for the four arms was statistically significant ( P = 0.027). However, no statistically significant differences were found in PFS or overall survival between NHT vs. AHT and WPRT compared with PORT. A trend towards a difference was found in PFS ( P = 0.065) in favor of the WPRT + NHT arm compared with the PORT + NHT and WPRT + AHT arms. Unexpected interactions appear to exist between the timing of hormonal therapy and radiation field size for this patient population. Four Phase III trials have demonstrated better outcomes when NHT was combined with RT compared with RT alone. The Radiation Therapy Oncology Group's 9,413 trial results have demonstrated that when NHT is used in conjunction with RT, WPRT yields a better PFS than does PORT. It also showed that when NHT + WPRT results in better overall survival than does WPRT + short-term AHT. Additional studies are warranted to determine whether the failure to demonstrate an advantage for NHT + WPRT compared with PORT + AHT is chance or, more likely, reflects a previously unrecognized biologic phenomenon.

Improved Outcomes With Higher Doses for Salvage Radiotherapy After Prostatectomy

To evaluate relapse-free survival with higher doses for patients receiving salvage radiotherapy (RT) after radical prostatectomy (RP). A total of 122 patients with pathologically negative lymph nodes received salvage RT after RP from 1984 to 2004. Median prostate bed dose was 60 Gy for 38 patients and 70 Gy for 84 patients. Four months of total androgen suppression and whole-pelvic RT were given concurrently to 68 and 72 patients, respectively. The median follow-up was >5 years. Kaplan-Meier and Cox proportional hazards multivariable analyses were performed for all clinical, pathologic, and treatment factors predicting for biochemical relapse-free survival (bRFS). There were 60 biochemical failures after salvage RT, with a median time to failure of 1.2 years. A dose response was observed, with a 5-year bRFS rate of 25% vs. 58% for prostate bed doses of 60 Gy vs. 70 Gy (p < 0.0001). For patients receiving RT alone the 5-year bRFS rate was 17% vs. 55% (p = 0.016), and for those receiving prostate-bed-only RT it was 23% vs. 66% (p = 0.037) for doses of 60 Gy vs. 70 Gy, respectively. On multivariate analysis a prostate bed dose of 70 Gy (p = 0.012, hazard ratio [HR] 0.48 [95% Confidence Interval (CI), 0.27-0.87]), pre-RT prostate-specific antigen value < or =1 ng/mL (p < 0.0001, HR 0.28 [95% CI, 0.16-0.48]), and lack of seminal vesicle involvement (p = 0.009, HR 0.44 [95% CI, 0.26-0.77]) remained independently significant. A clinically significant dose response from 60 Gy to 70 Gy was observed in the setting of salvage RT after prostatectomy. A dose of 70 Gy to the prostate bed is recommended to achieve optimal disease-free survival.

Postoperative Prostate-Specific Antigen Velocity Independently Predicts for Failure of Salvage Radiotherapy After Prostatectomy

Identification of patients most likely to benefit from salvage radiotherapy (RT) using postoperative (postop) prostate-specific antigen (PSA) kinetics. From 1984 to 2004, 81 patients who fit the following criteria formed the study population: undetectable PSA after radical prostatectomy (RP); pathologically negative nodes; biochemical relapse defined as a persistently detectable PSA; salvage RT; and two or more postop PSAs available before salvage RT. Salvage RT included the whole pelvic nodes in 55 patients and 4 months of total androgen suppression in 56 patients. The median follow-up was >5 years. All relapses were defined as a persistently detectable PSA. Kaplan-Meier and Cox proportional hazards multivariable analysis were performed for all clinical, pathological, and treatment factors predicting for biochemical relapse-free survival (bRFS). There were 37 biochemical relapses observed after salvage RT. The 5-year bRFS after salvage RT for patients with postop prostate-specific antigen velocity < or = 1 vs. >1 ng/ml/yr was 59% vs. 29%, p = 0.002. In multivariate analysis, only postop PSAV (p = 0.0036), pre-RT PSA level < or = 1 (p = 0.037) and interval-to-relapse >10 months (p = 0.012) remained significant, whereas pelvic RT, hormone therapy, and RT dose showed a trend (p = approximately 0.06). PSAV, but not prostate-specific antigen doubling time, predicted successful salvage RT, suggesting an association of zero-order kinetics with locally recurrent disease. Postoperative PSA velocity independently predicts for the failure of salvage RT and can be considered in addition to high-risk features when selecting patients in need of systemic therapy following biochemical failure after RP. For well-selected patients, salvage RT can achieve high cure rates.

An Update of the Phase III Trial Comparing Whole Pelvic to Prostate Only Radiotherapy and Neoadjuvant to Adjuvant Total Androgen Suppression: Updated Analysis of RTOG 94-13, With Emphasis on Unexpected Hormone/Radiation Interactions

This trial was designed to test the hypothesis that total androgen suppression and whole pelvic radiotherapy (WPRT) followed by a prostate boost improves progression-free survival (PFS) by > or =10% compared with total androgen suppression and prostate only RT (PORT). This trial was also designed to test the hypothesis that neoadjuvant hormonal therapy (NHT) followed by concurrent total androgen suppression and RT improves PFS compared with RT followed by adjuvant hormonal therapy (AHT) by > or =10%. Patients eligible for the study included those with clinically localized adenocarcinoma of the prostate and an elevated prostate-specific antigen level of <100 ng/mL. Patients were stratified by T stage, prostate-specific antigen level, and Gleason score and were required to have an estimated risk of lymph node involvement of >15%. The difference in overall survival for the four arms was statistically significant (p = 0.027). However, no statistically significant differences were found in PFS or overall survival between NHT vs. AHT and WPRT compared with PORT. A trend towards a difference was found in PFS (p = 0.065) in favor of the WPRT + NHT arm compared with the PORT + NHT and WPRT + AHT arms. Unexpected interactions appear to exist between the timing of hormonal therapy and radiation field size for this patient population. Four Phase III trials have demonstrated better outcomes when NHT was combined with RT compared with RT alone. The Radiation Therapy Oncology Group 9413 trial results have demonstrated that when NHT is used in conjunction with RT, WPRT yields a better PFS than does PORT. It also showed that when NHT + WPRT results in better overall survival than does WPRT + short-term AHT. Additional studies are warranted to determine whether the failure to demonstrate an advantage for NHT + WPRT compared with PORT + AHT is chance or, more likely, reflects a previously unrecognized biologic phenomenon.

Radiotherapy After Prostatectomy: Improved Biochemical Relapse-Free Survival With Whole Pelvic Compared With Prostate Bed Only for High-Risk Patients

To compare the biochemical relapse-free survival (bRFS) among patients receiving whole pelvic radiotherapy (WPRT) vs. prostate bed RT (PBRT) after radical prostatectomy. Between 1985 and 2005, 160 patients underwent adjuvant or salvage RT after radical prostatectomy. A short course of total androgen suppression was also given concurrently to 87 patients. Of the 160 patients, 114 were considered at high risk of lymph node involvement because they had a pathologic Gleason score of >/=8, a preoperative prostate-specific antigen level >20 ng/mL, seminal vesicle or prostate capsule involvement, or pathologic lymph node involvement. Of this group, 72 underwent WPRT and 42 underwent PBRT. The median follow-up was >5 years for all patient subsets. Kaplan-Meier and Cox proportional hazards multivariate analyses were performed for all clinical, pathologic, and treatment factors predicting for bRFS. Whole pelvic RT resulted in superior bRFS compared with PBRT (p = 0.03). The advantage of WPRT was limited to high-risk patients, with a 5-year bRFS rate of 47% (95% confidence interval, 35-59%) after WPRT vs. 21% (95% confidence interval, 8-35%) after PBRT (p = 0.008). For low-risk patients, no difference (p = 0.9) was found. On multivariate analysis, only WPRT (p = 0.02) and a preoperative prostate-specific antigen level <1.0 ng/mL (p = 0.002) were significantly associated with bRFS. The benefit from total androgen suppression with postoperative RT was only observed when given concurrently with WPRT (p = 0.04) and not with PBRT (p = 0.4). The results of our study have indicated that WPRT confers superior bRFS compared with PBRT for high-risk patients receiving adjuvant or salvage RT after radical prostatectomy. This advantage was observed only with concurrent TAS. These results are analogous to the benefit from WPRT seen in the Radiation Therapy Oncology Group 94-13 study.

An Update of the Phase III Trial Comparing Whole-Pelvic (WP) to Prostate Only (PO) Radiotherapy and Neoadjuvant to Adjuvant Total Androgen Suppression (TAS): Updated Analysis of RTOG 94-13

An Update of the Phase III Trial Comparing Whole-Pelvic (WP) to Prostate Only (PO) Radiotherapy and Neoadjuvant to Adjuvant Total Androgen Suppression (TAS): Updated Analysis of RTOG 94-13

Economic analysis of a phase III clinical trial evaluating the addition of total androgen suppression to radiation versus radiation alone for locally advanced prostate cancer (Radiation Therapy Oncology Group protocol 86-10)

To evaluate the cost-effectiveness of adding hormone therapy to radiation for patients with locally advanced prostate cancer, using a Monte Carlo simulation of a Markov Model. Radiation Therapy Oncology Group (RTOG) protocol 86-10 randomized patients to receive radiation therapy (RT) alone or RT plus total androgen suppression (RTHormones) 2 months before and during RT for the treatment of locally advanced prostate cancer. A Markov model was designed with Data Pro (TreeAge Software, Williamstown, MA). The analysis took a payer's perspective. Transition probabilities from one state of health (i.e., with no disease progression or with hormone-responsive metastatic disease) to another were calculated from published rates pertaining to RTOG 86-10. Patients remained in one state of health for 1 year. Utility values for each health state and treatment were obtained from the literature. Distributions were sampled at random from the treatment utilities according to a second-order Monte Carlo simulation technique. The mean expected cost for the RT-only treatments was 29,240 dollars (range, 29,138-29,403 dollars). The mean effectiveness for the RT-only treatment was 5.48 quality-adjusted life years (QALYs) (range, 5.47-5.50). The mean expected cost for RTHormones was 31,286 dollars (range, 31,058-31,555 dollars). The mean effectiveness was 6.43 QALYs (range, 6.42-6.44). Incremental cost-effectiveness analysis showed RTHormones to be within the range of cost-effectiveness at 2,153 dollars/QALY. Cost-effectiveness acceptability curve analysis resulted in a >80% probability that RTHormones is cost-effective. Our analysis shows that adding hormonal treatment to RT improves health outcomes at a cost that is within the acceptable cost-effectiveness range.

Docetaxel Followed by Hormone Therapy in Men Experiencing Increasing Prostate-Specific Antigen After Primary Local Treatments for Prostate Cancer

Prostatectomy or radiation for localized prostate cancer (PC) can fail in up to 15% to 30% of patients. The purpose of this study was to determine feasibility, tolerability, and outcome of docetaxel followed by hormone therapy in men experiencing an increasing prostate-specific antigen (PSA) after their primary local treatments for PC. Men with increasing serum PSA after prostatectomy or/and radiation were eligible. Serum PSA had to be > or = 4 ng/mL and serum testosterone had to be in the noncastrate range. Treatment included docetaxel 70 mg/m2 every 3 weeks for up to six cycles, followed by total androgen suppression (luteinizing hormone-releasing hormone agonist plus bicalutamide) and peripheral androgen blockade (finasteride plus bicalutamide) for 12 to 20 months. Thirty-nine men were enrolled; 32 had PSA-only failure, seven also had clinical metastasis. Baseline median PSA was 13.7 ng/mL. Serum PSA decreased > or = 50% in 17 of 35 patients (48.5%) and > or = 75% in seven of 35 patients (20%) with docetaxel. The PSA decreased to a median of 0.1 ng/mL with subsequent hormone therapy. In 28 of 33 patients the PSA increased (median, 0.41 ng/mL) at a median follow-up of 2.3 months after treatment. In contrast, in five of 33 men the PSA remains at 0.1 ng/mL at a median of 18.9 months after therapy; three of these five men had soft tissue metastasis at entry but remain in complete remission. The most common grade 3 to 4 toxicity was neutropenia (61.5%). Docetaxel followed by hormone therapy of limited duration may provide disease control in subgroups of men experiencing failure after local treatments for PC.

Evaluating the Addition of Total Androgen Suppression to Radiation versus Radiation Alone for Locally Advanced Prostate Cancer

Evaluating the Addition of Total Androgen Suppression to Radiation versus Radiation Alone for Locally Advanced Prostate Cancer

Radiotherapy after radical prostatectomy: Does transient androgen suppression improve outcomes?: King CR, Presti JC Jr, Gill H, Brooks J, Hancock SL, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA. Int J Radiat Oncol Biol Phys 2004;59:341–7

Purpose The long-term biochemical relapse-free survival and overall survival were compared for patients receiving either radiotherapy (RT) alone or radiotherapy combined with a short-course of total androgen suppression for failure after radical prostatectomy. Methods and materials Between 1985 and 2001, a total of 122 patients received RT after radical prostatectomy at our institution. Fifty-three of these patients received a short-course of total androgen suppression (TAS) 2 months before and 2 months concurrent with RT with a nonsteroidal antiandrogen and an luteinizing hormone-releasing hormone (LHRH) agonist (combined therapy group); the remaining 69 patients received RT alone. Treatment failure was defined after postoperative RT as a detectable PSA >0.05 ng/ml. Clinical and treatment variables examined included: presurgical PSA, clinical T stage, pathologic Gleason sum (pGS), seminal vesicle (SV) involvement, lymph node involvement, surgical margins, pre-RT PSA, prostate dose, pelvic irradiation, indication for postoperative RT (salvage or adjuvant), and time interval between surgery and RT. Minimum follow-up after postoperative RT was 1 year and median follow-up was 5.9 years (maximum, 14 years) for patients receiving RT alone, and 3.9 years (maximum, 11 years) for patients receiving RT with TAS (combined therapy group). Kaplan-Meier analysis was performed for PSA failure-free survival (bNED) and for overall survival (OS). Cox proportional hazards multivariable analysis examined the influence all clinical and treatment variables predicting for bNED and OS. Results The median time to PSA failure after postoperative RT was 1.34 years for the combined therapy group and 0.97 years for the RT alone group (p = 0.19), with no failures beyond 5 years. At 5 years, the actuarial bNED rates were 57% for the combined therapy group compared with 31% for the RT alone group (p = 0.0012). Overall survival rates at 5 years were 100% for the combined therapy group compared with 87% for the RT alone group (p = 0.0008). For pGS ⩽7, the 5-year bNED rates were 58% for combined therapy and 38% for RT alone (p = 0.0155), and for pGS ⩾8 the 5-year bNED rates were 65% for combined therapy and 17% for RT alone (p = 0.075). The 5-year OS rates for pGS ⩽7 were 100% for combined therapy and 98% for RT alone group (p = 0.106), and the 5-year OS for pGS ⩾8 was 100% for combined therapy and 54% for RT alone (p = 0.04). On multivariable analysis, only SV involvement (p = 0.0145) and the addition of short-course TAS to postoperative RT (p = 0.0019) were significant covariates predicting for bNED and, similarly, approached significance for overall survival (p = 0.0594 and p = 0.0856, respectively). Conclusions Radiotherapy combined with a short-course TAS after radical prostatectomy appears to confer a PSA relapse-free survival advantage and possibly an overall survival advantage when compared with RT alone. The hypothesis that a transient course of androgen suppression with salvage or adjuvant RT after prostatectomy improves outcomes will need to be tested in a randomized trial.

Phase II study of combined external beam radiation therapy (EBRT), brachytherapy (PB), total androgen suppression (TAS), and adjuvant docetaxel (AD) in poor-risk, localized prostate cancer (PCa)

4764 Background: Encouraging responses rates to Docetaxel in advanced PCa have been shown. However, our understanding of Docetaxel with radiation in localized PCa is limited. This prospective, phase II study evaluates the efficacy and safety of AD when combined with EBRT, PB, and TAS in high-risk, localized PCa. Methods: Inclusion criteria: T3/T4, or Gleason score (GS) 7 and PSA >10 or GS 8–10 and PSA >7 without extrapelvic disease, no prior chemotherapy or EBRT, no prior androgen deprivation, KPS ≥ 70%, and adequate hepatic, renal, cardiac, and bone marrow reserve. Patients received pelvic EBRT (45.0Gy) followed by a permanent PB implant 4 weeks after EBRT. AD was started 1 month after PB at 35 mg/m2 weekly x 3 q 4wks x 3 mos. TAS (anti-androgen x 4 wks and LHRH x 2 yrs) started day 1 of EBRT. Results: 36 patients have been enrolled from 6/00–11/03. One pt discontinued after EBRT and another pt refused chemotherapy resulting in 34 evaluable for this report. Median age was 63 years (51–78), median baseline PSA 17.8 (1.2–84.6) and a GS of 8–10 in 50%. PSA relapse-free survival (PRFS) time was calculated from the date of EBRT initiation to the date of last PSA in 2003. The median follow-up time of PRFS was 20 months (range: 1–32 months). Since there have been no biochemical or clinical failures to date in the 34 evaluable patients, all PRFS times are censored (100% survival to date). Most toxicity was Grade 1–2 GU. Grade 3 GU toxicities: nocturia (3), and urinary frequency (3). No Grade 3 or higher GI toxicity occurred. Two patients experienced DVT's (one GR3 and one GR4). While receiving chemotherapy, Grade 3 toxicities included anemia (2) and leukopenia (2). Conclusions: Multi-modality therapy as described in this study was well tolerated for high-risk Pca. Although the follow-up interval is short, tumor control rates are very encouraging. Additional follow-up and patient accrual will be needed to validate these findings. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Pharmaceuticals

Phase II study of combined external beam radiation therapy (EBRT), brachytherapy (PB), total androgen suppression (TAS), and adjuvant docetaxel (AD) in poor-risk, localized prostate cancer (PCa)

4764 Background: Encouraging responses rates to Docetaxel in advanced PCa have been shown. However, our understanding of Docetaxel with radiation in localized PCa is limited. This prospective, phase II study evaluates the efficacy and safety of AD when combined with EBRT, PB, and TAS in high-risk, localized PCa. Methods: Inclusion criteria: T3/T4, or Gleason score (GS) 7 and PSA >10 or GS 8–10 and PSA >7 without extrapelvic disease, no prior chemotherapy or EBRT, no prior androgen deprivation, KPS ≥ 70%, and adequate hepatic, renal, cardiac, and bone marrow reserve. Patients received pelvic EBRT (45.0Gy) followed by a permanent PB implant 4 weeks after EBRT. AD was started 1 month after PB at 35 mg/m2 weekly x 3 q 4wks x 3 mos. TAS (anti-androgen x 4 wks and LHRH x 2 yrs) started day 1 of EBRT. Results: 36 patients have been enrolled from 6/00–11/03. One pt discontinued after EBRT and another pt refused chemotherapy resulting in 34 evaluable for this report. Median age was 63 years (51–78), median baselin...