Neoadjuvant Androgen Suppression Therapy Research Articles

Factors Associated With Reduction in Use of Neoadjuvant Androgen Suppression Therapy Before Radical Prostatectomy

To determine whether the prescribing patterns for nonindicated androgen suppression therapy (AST), using neoadjuvant AST as the model, changed according to the prevailing clinical evidence, changes in reimbursement, or evidence of increased harm from treatment. We identified 34,976 men with prostate cancer who had undergone radical prostatectomy within 12 months of diagnosis from the Surveillance, Epidemiology, and End Results-Medicare data set (1992-2007), and their clinical and demographic parameters were assessed. We measured the Medicare claims for receipt of AST before radical prostatectomy and calculated the annual rates of neoadjuvant AST, which were adjusted for confounding variables using multivariate logistic regression analysis, and compared them with the prevailing published clinical data on the outcomes of neoadjuvant AST, changes in reimbursement, or published data on clinical harm from treatment. The use of neoadjuvant AST increased from 7.8% in 1992 to a peak of 17.6% in 1996 and then decreased steadily to 4.6% in 2007. This rate change was significant on multivariate regression analysis, with a single join point in 1996 (P<.001), and corresponded to published data showing improved surgical margin rates and pathologic downstaging in the early 1990s and data showing no improvement in disease recurrence or overall survival beginning in 1997. Changes in reimbursement and evidence of harm from AST were not associated with the decreased use of neoadjuvant AST. Using neoadjuvant AST as the model for the nonindicated use of AST, physicians reduced ASTuse in response to high-level evidence showing a lack of benefit, despite the high reimbursement. This suggests that physicians adapt to emerging evidence and use evidence-based practice.

PSA Response to Tri-modality (HDR Brachytherapy, Hypofractionated 3D-CRT, Neoadjuvant/Adjuvant Androgen Therapy) Predicts Biochemical Progression-free Survival in Localized Prostate Cancer

High dose rate (HDR) brachytherapy combined with external beam radiation therapy (EBRT), neoadjuvant androgen suppression therapy (NAST) and adjuvant androgen suppression therapy (AAST) (Tri-modality) have been used to treat localized high risk prostate cancer. To define prognostic factors of biochemical relapse free survival (bRFS), an analysis of patients treated with Tri-modality were performed.

Risk Stratification after Biochemical Failure following Curative Treatment of Locally Advanced Prostate Cancer: Data from the TROG 96.01 Trial

Purpose. Survival following biochemical failure is highly variable. Using a randomized trial dataset, we sought to define a risk stratification scheme in men with locally advanced prostate cancer (LAPC). Methods. The TROG 96.01 trial randomized 802 men with LAPC to radiation ± neoadjuvant androgen suppression therapy (AST) between 1996 and 2000. Ten-year follow-up data was used to develop three-tier post-biochemical failure risk stratification schemes based on cutpoints of time to biochemical failure (TTBF) and PSA doubling time (PSADT). Schemes were evaluated in univariable, competing risk models for prostate cancer-specific mortality. The performance was assessed by c-indices and internally validated by the simple bootstrap method. Performance rankings were compared in sensitivity analyses using multivariable models and variations in PSADT calculation. Results. 485 men developed biochemical failure. c-indices ranged between 0.630 and 0.730. The most discriminatory scheme had a high risk category defined by PSADT < 4 months or TTBF < 1 year and low risk category by PSADT > 9 months or TTBF > 3 years. Conclusion. TTBF and PSADT can be combined to define risk stratification schemes after biochemical failure in men with LAPC treated with short-term AST and radiotherapy. External validation, particularly in long-term AST and radiotherapy datasets, is necessary.

PSA Response to Neoadjuvant Androgen Suppression Therapy Prior to High Dose Radiotherapy Predicts Survival in Clinically Localized High Risk Prostate Cancer

PSA Response to Neoadjuvant Androgen Suppression Therapy Prior to High Dose Radiotherapy Predicts Survival in Clinically Localized High Risk Prostate Cancer

Predictors of the Use of Supplemental Androgen Suppression Therapy (AST) and External Beam Radiation Therapy (EBRT) in Men with High-risk Prostate Cancer (PC) Undergoing Brachytherapy

Recent evidence suggests that both supplemental AST and EBRT may decrease prostate cancer specific mortality (PCSM) in men with high risk PC undergoing prostate brachytherapy (B) (JCO 27: 3923-8, 2009.) Therefore, we assessed patient- and tumor-related variables and temporal trends associated with both supplemental neoadjuvant AST and EBRT use compared with B alone in a community-based cohort of men with high-risk PC.

Androgen‐suppression therapy for prostate cancer and the risk of death in men with a history of myocardial infarction or stroke

To examine the effect of short-course androgen-suppression therapy (AST) before brachytherapy on all-cause mortality (ACM) rates, stratified by the presence or absence of a history of myocardial infarction (MI) or stroke. AST is used to reduce prostate size to enable men with favourable-risk prostate cancer to undergo brachytherapy, but no disease-specific benefit has been reported for this practice, and AST use has been associated with an increased risk of ACM in some men with pre-existing cardiovascular disease. The study comprised 12792 men with favourable-risk disease, i.e. a prostate-specific antigen (PSA) level of <20 ng/mL, Gleason score ≤7 and clinical category ≤T2c, treated between 1991 and 2007 at community-based medical centres with brachytherapy ± neoadjuvant AST. Multivariable Cox regression analysis was used to assess whether there were significant associations between AST use in men with a history of MI or stroke and the risk of ACM, adjusting for age, treatment year, and known prognostic factors of prostate cancer. After a median (interquartile range) follow-up of 3.8 (2.0-5.9) years there were 1557 deaths. The risk of ACM was lower in men with no history of MI or stroke than in those with this history, whether AST was used (adjusted hazard ratio 0.79, 95% confidence interval 0.67-0.92; P= 0.003) or not (0.74, 0.65-0.85; P < 0.001). However, men with a history of MI or stroke treated with AST had a greater risk of ACM than those not treated with AST (1.2, 1.05-1.38; P= 0.008). The use of short-course AST in men with a history of MI or stroke is associated with a greater risk of ACM in men with favourable-risk prostate cancer.

Five-year relapse-free survival and predictors of relapse following preoperative docetaxel and mitoxantrone for high-risk localized prostate cancer

5121 Background: Efforts to incorporate systemic therapy with activity against castration-resistant prostate cancer into the early management of high-risk disease are motivated by persistent risk of relapse when neoadjuvant androgen suppression therapy (AST) is combined with surgery. As docetaxel and mitoxantrone exert anti-tumor effects through distinct cellular mechanisms, this combination has the potential for synergistic activity against prostate cancer. Here we report the 5-year outcomes of patients treated with a novel regimen that combines these agents without AST prior to prostatectomy. We also examined pathologic, biomarker and clinical predictors of early relapse. Methods: 57 high-risk prostate cancer patients were enrolled in a phase I/II study of weekly docetaxel 35 mg/m2 and escalating mitoxantrone to 4 mg/m2 delivered weekly for 3 of every 4 weeks per cycle for 4 cycles over 16 weeks followed by radical prostatectomy. A tissue micro-array constructed from the prostatectomy specimens served to facilitate the exploratory evaluation of biomarkers. The primary end point was relapse-free survival. Relapse was defined as a confirmed serum PSA &gt; 0.4 ng/mL. Results: 54 of 57 pts received all 4 cycles of docetaxel and mitoxantrone prior to radical prostatectomy. Grade 4 toxicities were limited to leucopenia, neutropenia and hyperglycemia. Serum testosterone levels remained stable after chemotherapy. Negative surgical margins were attained in 67% of cases. Lymph node involvement was detected in 18.5% of cases. With a median follow-up of 63 months (range 7 to 86 months), 27 of 57 (47.4%) patients recurred. The Kaplan-Meier progression-free survival at 2 years was 65.5% (95% CI 53.0% to 78.0%) and 49.8% at 5 years (95% CI 35.5% to 64.1%). Pretreatment serum PSA, lymph node involvement, and post-chemotherapy tissue VEGF expression were independent predictors of early relapse. Conclusions: Preoperative combination chemotherapy with docetaxel and mitoxantrone is safe. Approximately half of the high risk pts remain relapse free at 5 years and clinical and molecular predictors of early relapse in this population have been identified. [Table: see text]

Short-course androgen suppression therapy prior to brachytherapy for favorable-risk prostate cancer and the risk of all-cause mortality in men with or without preexisting cardiovascular disease

5066 Background: AST is used to reduce prostate size in men with favorable-risk prostate cancer who have pubic arch interference in order to enable them to undergo prostate brachytherapy. While no disease-specific benefit has been demonstrated to AST in this setting, AST use has been associated with both cardiovascular morbidity and mortality. The Objective is to determine the effect of short-course androgen suppression therapy (AST) prior to brachytherapy on all cause mortality (ACM), stratified by the presence or absence of preexisting cardiovascular disease (CVD). Methods: The study cohort included 12,792 men with previously-untreated low or intermediate risk prostate cancer (PSA &lt; 20 ng/mL; Gleason score 7 or below on initial biopsy; clinical category T2c or below) treated between 1992 and 2005 at one of 21 community-based medical centers in Illinois, Florida, New York, or North Carolina. Men were treated with brachytherapy with or without neoadjuvant AST. Multivariate Cox regression analysis was performed to assess whether significant associations between preexisting CVD and ACM existed adjusting for age, year of treatment and known prostate cancer prognostic factors. Results: After a median follow up of 3.76 years (interquartile range, 2.03 to 5.92 years), 1557 deaths had occurred. The use of neoadjuvant AST was significantly associated with an increased risk of ACM in men with pretreatment CVD (adjusted hazard ratio (AHR) 1.62, 95% CI, 1.40 to 1.87, p &lt; 0.001) but not in men without CVD (AHR 1.06, 95% CI, 0.91 to 1.25, p = 0.5). In men with preexisting CVD, AST use was associated with an increased risk of ACM at 5 years compared to men with CVD who did not use AST (17.5% (95%CI, 15.57% to 19.64%) vs. 14.35% (95%CI, 12.80% to 16.06%), p &lt; 0.0001). Conclusions: Preexisting CVD is associated with an increased risk of death in men with favorable-risk prostate cancer treated with short-course AST prior to brachytherapy. No significant financial relationships to disclose.

Tumor Volume Changes on 1.5 Tesla Endorectal MRI During Neoadjuvant Androgen Suppression Therapy for Higher-Risk Prostate Cancer and Recurrence in Men Treated Using Radiation Therapy Results of the Phase II CALGB 9682 Study

We prospectively determined whether the change in tumor volume (TV) during 2 months of neoadjuvant androgen suppression therapy (nAST) measured using conventional 1.5 Tesla endorectal magnetic resonance imaging (eMRI) was associated with the risk of recurrence after radiation (RT) and 6 months of AST. Between 1997 and 2001, 180 men with clinical stage T1c-T3cN0M0 adenocarcinoma of the prostate were registered. Fifteen were found to be ineligible and the institutional MR radiologist could not assess the TV in 32, leaving 133 for analysis. Multivariable Cox regression analysis was used to assess whether a significant association existed between eMRI-defined TV progression during nAST and time to recurrence adjusting for prostate-specific antigen (PSA) level, Gleason score (8 to 10 or 7 vs. 6 or less) and stage (T3 vs. T1-2). After a median follow up of 6.7 years and adjusting for known prognostic factors, there was a significant increase in the risk of PSA failure (HR, 2.3 [95% CI, 1.1-4.5; p = 0.025) in men with eMRI-defined TV progression during nAST. Specifically, adjusted estimates of PSA failure were significantly higher (p = 0.032) in men with, compared with men without, eMRI-defined TV progression reaching 38% vs. 19%, respectively, by 5 years. Eradicating intraprostatic hormone refractory prostate cancer (HRPC) by maximizing local control and randomized trials assessing whether survival is improved when agents active against HRPC are combined with maximal local therapy are needed in men who progress based on eMRI during nAST.

Changes on endorectal MRI during neoadjuvant hormonal therapy for prostate cancer and biochemical outcome in men managed using radiation therapy: A prospective phase II Cancer and Leukemia Group B study

5072 Background: We prospectively determined whether changes in tumor volume (TV) on 1.5 Tesla endorectal magnetic resonance imaging (eMRI) during neoadjuvant androgen suppression therapy (AST) were associated with biochemical outcome after radiation and 6 months of AST. Methods: Between May, 1996 and April, 2001,180 men with T1c-T3c non-metastatic adenocarcinoma of the prostate cancer were registered. Fifteen were found to be ineligible leaving 165 men who had a eMRI TV measurement at baseline and following 2 months of neoadjuvant AST. An eMRI response was defined as &gt; 10% reduction in the volume of all lesions consistent with prostate cancer. In 32 men, the institutional MR radiologist could not completely assess the TV leaving 133 for analysis. A proportional hazards model was used to assess whether a significant association existed between eMRI response and time to prostate-specific antigen (PSA) failure following registration adjusting for PSA level (continuous), Gleason score (8 to 10 or 7 versus 6 or less) and stage (T3 versus T1, 2). PSA failure was defined as 2 consecutive rises of 0.2 above 1.0 ng/ml (PSA fail) and according to the 1997 and the 2006 American Society of Therapeutic Radiology and Oncology (ASTRO) consensus definitions. Results: The median age and PSA level of the study cohort were 70 years and 10.7 ng/ml respectively. An eMRI response was noted in 112 (84%) men and 85, 47, and 47 men experienced PSA failure based on the 1997, 2006 ASTRO consensus and PSA fail definitions respectively. After a median follow up of 6.7 years and adjusting for known prognostic factors, there was a statistically significant association between eMRI defined tumor response and time to PSA failure using the 1997 (p = 0.04) and 2006 (p = 0.009) ASTRO consensus definitions and a near significant association (p = 0.08) using PSA fail. Conclusion: Men lacking a &gt; 10% reduction in the eMRI defined TV during neoadjuvant AST are at increased risk for recurrence following radiation and AST. Therefore, eMRI enables the early documentation of androgen insensitive disease and identifies men for trials evaluating outcome when non-AST based approaches are combined with radiation and AST. No significant financial relationships to disclose.

Acute Morbidity of Proton Therapy for Prostate Cancer: The Hyogo Ion Beam Medical Center Experience

To investigate the incidence and influencing factors of acute genitourinary (GU) and gastrointestinal morbidities in patients with prostate cancer treated with proton therapy. A total of 287 patients with histologically proven Stage cT1-T4N0M0 prostate cancer were treated with proton therapy between 2003 and 2004. Of these, 204 (71%) received neoadjuvant androgen suppression therapy. The patients were treated with 190-230-MeV protons using lateral-opposed techniques to a dose of 74 GyE. Dose-volume histogram analyses were performed. The incidence of acute morbidity was evaluated using the National Cancer Institute Common Toxicity Criteria, version 2.0. Clinical factors, including age, clinical target volume, initial prostate-specific antigen level, T stage, presence of diabetes mellitus, and the use of androgen suppression therapy, were investigated to determine whether those affected the incidence of acute GU morbidity. None developed Grade 2 or higher acute gastrointestinal morbidity. In contrast, 111 (39%) and 4 (1%) patients experienced acute Grade 2 and Grade 3 GU morbidities, respectively. However, 87% of the patients were successfully relieved by the administration of a selective alpha-1 blocker. Multivariate analysis showed that a larger clinical target volume (p = 0.001) and the use of androgen suppression therapy (p = 0.017) were significant factors for the prediction of acute Grade 2-3 GU morbidity. In our experience with proton therapy, a low incidence of acute gastrointestinal morbidity was observed. In contrast, the incidence of acute GU morbidity was similar to that in other reports of photon radiotherapy. Additional follow-up is warranted to elucidate the long-term safety and efficacy of proton therapy for prostate cancer.

Toward the Optimal Use of Androgen Suppression Therapy in the Radiotherapeutic Management of Prostate Cancer

Toward the Optimal Use of Androgen Suppression Therapy in the Radiotherapeutic Management of Prostate Cancer

Hemoglobin levels do not predict biochemical outcome for localized prostate cancer treated with neoadjuvant androgen-suppression therapy and external-beam radiotherapy

To investigate whether hemoglobin (Hb) levels affect outcome in men with localized prostate adenocarcinoma (LPA) treated with neoadjuvant androgen-suppression therapy (NAST) and external-beam radiotherapy (EBRT). A total of 563 men with LPA treated with NAST (median: 5.3 months) and EBRT who had Hb levels during treatment were retrospectively reviewed. Patient, tumor, and treatment variables, including the following Hb variables, were subjected to univariate and multivariable analyses to identify factors that predict biochemical control (bNED) and overall survival (OS): pre-EBRT Hb, Hb nadir during EBRT, and change in Hb from pre-EBRT to nadir during EBRT. Median PSA follow-up was 4.25 years. Forty-nine percent of men were anemic during EBRT, with a median Hb of 13.4 g/dL, and 68% experienced a decline in Hb from pre-EBRT to during EBRT of median 0.6 g/dL. Five-year Nadir+2 bNED and OS rates were similar for anemic and nonanemic patients during EBRT. High percent-positive biopsies, PSA and Gleason score, and use of AA monotherapy predicted worse bNED. High stage and age predicted worse OS. Hb variables were not predictive of bNED or OS. Anemia is a common side effect of NAST and is usually mild. Hb levels, however, do not predict biochemical control or survival.

Patient-reported acute gastrointestinal toxicity in men receiving 3-dimensional conformal radiation therapy for prostate cancer with or without neoadjuvant androgen suppression therapy

Objective To investigate the impact of 2 months of neoadjuvant and 2 months of concurrent hormonal therapy on the acute gastrointestinal (GI) toxicities associated with 3-dimensional conformal radiation therapy (3D-CRT) for prostate adenocarcinoma. Methods The study cohort consisted of 80 men who underwent 3D-CRT with ( n = 40) or without ( n = 40) neoadjuvant and concurrent hormonal therapy. Computerized tomography-based planning occurred after neoadjuvant hormonal therapy. All patients completed a previously validated, quality-of-life self-assessment tool on 7 GI symptoms, including diarrhea, urgency, pain, rectal bleeding, cramping, mucus, and tenesmus, at baseline and weekly during radiation therapy. Results Patients who received hormonal therapy were more likely to have T2b, T2c, T3a, or T3b ( P < 0.001) or Gleason score 7, 8, or 9 ( P = 0.02) disease compared to those that did not. The dose delivered to the planning target volume was 70 Gy for both groups. Median radiation treatment volume was numerically smaller for the hormone group but not to a statistically significant degree (949 vs. 1043 cc, P = 0.30). Patients who received hormonal therapy had less rectal pain ( P < 0.01) and tenesmus ( P = 0.02) but more rectal mucus ( P = 0.03) compared to those who did not. Conclusions Prostate gland volume reduction after androgen suppression therapy may reduce patient-reported acute GI toxicities associated with 3D-CRT for prostate cancer.

Quantifying the change in endorectal magnetic resonance imaging-defined tumor volume during neoadjuvant androgen suppression therapy in patients with prostate cancer

ObjectivesTo quantify the changes seen in the endorectal magnetic resonance imaging (erMRI)-defined prostate volume, predominant tumor volume, and secondary tumor volume during neoadjuvant total androgen suppression (TAS). MethodsBetween July 1997 and April 2001, 152 consecutive patients with clinical Stage T1b-T3cNXM0 prostate cancer were treated with 6 months of TAS and external beam radiotherapy. erMRI was conducted before and after 2 months of neoadjuvant TAS. The median values and percentage of changes in the erMRI-measured prostate volume and primary and secondary tumor volumes during neoadjuvant TAS were calculated and compared, using the Wilcoxon matched-pairs signed-rank method, for the patients overall and stratified by pretreatment risk group. ResultsAll patients had a significant decline in their erMRI-defined median prostate volume (36.6 versus 25.7 cm3, P <0.0001) during 2 months of neoadjuvant TAS. The median primary tumor volume decreased significantly in the intermediate-risk (0.77 versus 0.52 cm3, P <0.0001) and high-risk (2.48 versus 0.83 cm3, P <0.0001) patients. The median secondary tumor volume approached a significant decline in only the high-risk patients (0.45 versus 0.31 cm3, P = 0.15). Fourteen percent of patients had an increase in their primary tumor volume during neoadjuvant TAS. ConclusionsThe erMRI-defined primary and secondary tumor volumes generally decreased in the study population during neoadjuvant TAS. However, 14% of patients had an increase in their primary tumor volume during androgen suppression therapy. The clinical significance of this awaits further study.

Initial decline in hemoglobin during neoadjuvant hormonal therapy predicts for early prostate specific antigen failure following radiation and hormonal therapy for patients with intermediate and high-risk prostate cancer.

Declines in serum hemoglobin (Hgb) levels occur from the use of androgen suppression therapy (AST) in the treatment of prostate cancer patients. We studied whether time to prostate specific antigen (PSA) failure following external beam radiation therapy (RT) and AST could be predicted by the rate of decline in the Hgb level following the administration of neoadjuvant AST or by the Hgb level at presentation or at the start of RT. The study cohort comprised 110 intermediate or high-risk prostate cancer patients who were managed using three-dimensional conformal RT (70 Gy) and 6 months of AST (2 months neoadjuvant, concurrent, and adjuvant). A Cox regression multivariable analysis was performed to evaluate the ability of the rate of decline of the Hgb from baseline to the start of RT, baseline PSA level, Gleason score, percent positive biopsies, and T-category to predict time to PSA failure. A decline in the Hgb level of 1 g/dL or more during the first month of AST was the only significant predictor of time to PSA failure (P = 0.02) on multivariable analysis. The relative risk of PSA failure (95% confidence interval) for patients with a decline in Hgb level during the first month (> or = 1 g/dL vs. < 1 g/dL) was 6.3 (2.4, 8.3) and the 3-year estimate of PSA outcome was 66% versus 82% (P = 0.04), respectively. There were no imbalances in the pretreatment prognostic factors or length of follow-up in each of these groups. A decline of 1 g/dL or more in Hgb level during the first month of neoadjuvant AST was a predictor of early PSA failure following RT and AST in intermediate and high-risk prostate cancer patients.

Assessment of prostate cancer volume using endorectal coil magnetic resonance imaging: a new predictor of tumor response to neoadjuvant androgen suppression therapy

Objectives. A clinical tool that can reliably assess prostate cancer response to androgen suppression is lacking. This pilot study was designed to identify the potential clinical factor(s) that correlate with tumor response after neoadjuvant therapy. Methods. Twenty-one patients managed with definitive local therapy and neoadjuvant androgen suppression (median 3 months [range 2 to 7]) between 1995 and 1997 comprise the study population. Fisher's exact test was used to test the significance of the proportion of patients with a given clinical factor and the outcome of pathologic organ-confined disease. The clinical factors tested included preoperative prostate-specific antigen, biopsy Gleason score, clinical stage, months of total androgen suppression, the change in the endorectal magnetic resonance imaging (erMRI)-defined stage, the change in erMRI-defined tumor, and the change in the erMRI-defined prostate volume during neoadjuvant androgen suppression. Results. All 21 patients had a decrease in the erMRI-determined prostate volume and prostate-specific antigen during androgen suppression, whereas only 10 of 21 (48%) had a reduction in the erMRI-determined tumor volume. There was a statistically significant increased proportion of patients with a decrease in the erMRI-determined tumor volume ( P = 0.008) who had pathologic organ-confined disease. Conclusions. The results of this pilot study suggest that the changes in the erMRI-determined tumor volume occurring during androgen suppression may be predictive of the tumor response. Validation in a larger prospective study is currently underway.