Prostate-specific Antigen Decline Rate Research Articles

Gleason Pattern 5 May Be a Prognostic Factor in Radium-223 Treatment.

Radium-223 treatment reduces the risk of death in patients with metastatic castration-resistant prostate cancer (CRPC). This study analyzed the prognostic factors in patients treated with radium-223 dichloride. Patients who received radium-223 dichloride were retrospectively analyzed. Prostate-specific antigen (PSA) response and alkaline phosphatase (ALP) decline rates were analyzed. Overall survival (OS) was evaluated using Kaplan-Meier curves, and prognostic factors for OS were assessed using Cox proportional hazards analysis. Fifty-six patients were included in the study. The five-year OS rate in patients after diagnosis of CRPC was 62.2% [95% confidence interval (CI)=27.55-112.45], while the five-year OS rate in patients at the initiation of radium-223 treatment was 21.3% (95%CI=17.20-36.79). Six patients (11.1%) had a >50% PSA decline rate, and 10 (17.9%) had a >50% ALP decline rate. Cox proportional hazards analysis showed that PSA levels at the initiation of radium-223 treatment [hazard ratio (HR)=1.00; 95%CI=1.00-1.00; p=0.0054] and Gleason Pattern (GP) 5 (HR=5.42; 95%CI=1.08-27.27; p=0.0400) were associated with OS. Patients with GP 5 had a significantly poorer prognosis compared with patients with a GP ≤4. Early administration of radium-223 as a first- or second-line treatment was not associated with OS compared with late administration of radium-223 as a third-line or later treatment. GP 5 and high PSA levels at radium-223 initiation were associated with worse OS. Radium-223 as first- or second-line treatment was not associated with OS. Therefore, a treatment strategy for CRPC based on GP 5 is needed.

A preliminary study on the diagnostic value of PSADR, DPC and TSRP in the distinction of prostatitis and prostate cancer

BackgroundThe purpose of this study was to investigate the ability of differential diagnosis of prostate specific antigen decline rate (PSADR) per week, degree of prostatic collapse (DPC) and tissue signal rate of prostate (TSRP) between prostatitis and prostate cancer.MethodsThe clinical data of 92 patients [prostate specific antigen (PSA) > 10 ng/mL] who underwent prostate biopsy in the Department of Urology, the Second Affiliated Hospital of Xi ’an Jiaotong University from May 2017 to April 2020 were reviewed retrospectively. They were divided into two groups, prostatitis group (n = 42) and prostate cancer (PCa) group (n = 50), according to pathological results. Parameters, like patient characteristics, PSADR, DPC, TSRP and infectious indicators, were compared and analyzed by t test or non-parametric test to identify if there were significant differences. The thresholds of parameters were determined by the receiver operating characteristic curve (ROC), and the data were analyzed to investigate the diagnostic value in distinguishing of prostatitis and prostate cancer.ResultsThere were statistical differences in age, PSADR, DPC, TSRP, neutrophil percentage in serum, white blood cell (WBC) in urine and prostate volume between prostatitis group and PCa group (P < 0.001, < 0.001, = 0.001, 0.001, 0.024, 0.014, < 0.001 respectively). There was no statistical difference in serum WBC count, serum neutrophil count, monocyte percentage and urine bacterial count between two groups (P = 0.089, 0.087, 0.248, 0.119, respectively). Determined by ROC curve, when the thresholds of PSADR per week as 3.175 ng/mL/week, DPC as 1.113, TSRP as 2.708 were cutoffs of distinguishing prostatitis and prostate cancer. When combining these three indexes to diagnose, the accuracy rate of diagnosis of prostatitis was 78.85%, the accuracy rate of diagnosis of prostate cancer was 97.50%. Univariate analysis suggested that PSADR, DPC and TSRP played an important role in differentiating prostate cancer from prostatitis (P < 0.05), multivariate analysis suggested PSADR > 3.175 might be good indicators when distinguishing prostate disease with prostatitis (OR = 14.305, 95%CI = 3.779 ~ 54.147), while DPC > 1.113 and TSRP > 2.708 might be associated with a higher risk of prostate cancer (OR = 0.151, 95%CI = 0.039 ~ 0.588; OR = 0.012, 95%CI = 0.005 ~ 0.524, respectively).ConclusionThe combination of PSADR per week, DPC, and TSRP might be helpful to distinguish prostate cancer and prostatitis, and can reduce unnecessary invasive and histological procedure.

Multiple Docetaxel Retreatments Without Prednisone for Metastatic Castration-Resistant Prostate Cancer in the Docetaxel-Only Era: Effects on PSA Kinetics and Survival.

IntroductionThis study aimed to assess the effects of multiple docetaxel (DOC) treatments on prostate-specific antigen (PSA) kinetics and survival among patients with metastatic castration-resistant prostate cancer (mCRPC) who were sensitive to first-line DOC and received no other life-prolonging agents. To eliminate the effect of cortisone on serum PSA, only patients who were treated without prednisone were included.MethodsThis IRB-approved retrospective study evaluated 52 patients with mCRPC who were retreated using DOC after first-line DOC (without prednisone in both cases), based on a PSA response of > 50% and no radiographic progression. Twenty-three PSA-based factors, including static and kinetic PSA measures, were evaluate for their ability to predict overall survival (OS)ResultsThe patients received 688 cycles of DOC in 143 series, including 91 courses of retreatments (1 cycle: 28 patients, 2 cycles: 14 patients, 3 cycles: 8 patients, 4 cycles: 1 patient, and 7 cycles: 1 patient). The median overall number of cycles per patient was 12 (range: 7–31). The median durations of the first, second, and third holidays were 18 weeks (6–60 weeks), 16 weeks (3–44 weeks), and 17 weeks (8–51 weeks), respectively. The median OSs were 22 months (10.5–70 months) after the first DOC treatment and 14 months (3–65 months) after the second DOC treatment. The > 50% PSA decline rate was 48% after retreatment. Short treatment holidays (< 3 months) were associated with shortened OS (p = 0.01). In the multivariate analysis, a 25% PSA increase over the nadir was the strongest predictor of survival (HR: 3.20, 95% CI: 1.47–6.99, p = 0.003).ConclusionsDOC retreatment without prednisone had anti-tumor activity in a considerable proportion of mCRPC cases that were initially sensitive to first-line DOC. A 25% PSA increase over the nadir might predict acquired DOC resistance.

Efficacy of cabazitaxel and the influence of clinical factors on the overall survival of patients with castration-resistant prostate cancer: A local experience of a multicenter retrospective study.

To date, the optimal sequencing of life-prolonging therapies for patients with metastatic castration-resistant prostate cancer (mCRPC) remains unclear owing to a lack of prospective trials. This study aimed to evaluate the efficacy and safety of cabazitaxel (CBZ) treatment and examine the prognostic factors for oncological outcomes in patients with mCRPC who received CBZ after docetaxel (DOC). This multi-institutional retrospective study included 44 patients with mCRPC who received CBZ. All enrolled patients had histologically confirmed prostate cancer (PCa) with distant metastases and had received DOC before CBZ administration. The primary endpoint was the oncological outcomes, including the overall (OS) and progression-free survival (PFS). The secondary endpoints were adverse events due to CBZ and rates of ≥30% reduction in prostate-specific antigen (PSA) levels. The median follow-up period was 9.2 months (range, 0.2-34 months). During this time, 34 patients (77%) died of PCa. The median OS and PFS were 12.2 (range, 0.2-34 months) and 1.4 months (range, 0.4-17 months), respectively. According to the PSA decline rate, patients who achieved a ≥30% reduction in PSA levels had significantly longer OS than those who showed a<30% reduction in PSA levels (P=0.002). Regarding the number of cycles of CBZ, patients who received ≥4 cycles of CBZ showed significantly longer OS than those who received<4 cycles of CBZ (P<0.001). Patients who had visceral metastasis showed significantly shorter OS than those without visceral metastasis (P=0.012). This study demonstrated that CBZ was effective and safe in Japanese local patients in a real-world setting. Patients with mCRPC who received ≥4 cycles of CBZ showed a ≥30% reduction in the serum PSA levels, and did not have visceral metastasis might achieve longer OS.

Long-term results and PSA kinetics after robotic SBRT for prostate cancer: multicenter retrospective study in Korea (Korean radiation oncology group study 15\u201301)

BackgroundTo evaluate the treatment outcome and prostate-specific antigen (PSA) change after stereotactic body radiotherapy (SBRT) for localized prostate cancer.MethodsPatients with localized prostate cancer treated with SBRT at three academic hospitals were enrolled. Treatment was delivered using Cyberknife with dose range from 35 to 37.5 Gy in 5 fractions. Biochemical failure (BCF) was assessed with Phoenix definition and toxicities were scored with Radiation Therapy Oncology Group (RTOG) toxicity criteria. The PSA kinetics were analyzed in patients who received no androgen deprivation therapy (ADT) and showed no recurrence.ResultsOf the total 88 patients, 14 patients (15.9%) received ADT. After median follow-up of 63.8 months, the 5-year BCF free survival (BCFFS) was 94.7%. Two patients experienced late grade ≥ 3 GI toxicities (2.2%). The median nadir PSA was 0.12 ng/mL (range, 0.00–2.62 ng/mL) and the median time to nadir was 44.8 months (range, 0.40–85.7 months). Patients who reached nadir before 24 months showed poorer BCFFS than the others. The rate of PSA decline was maximum in the first year after treatment and gradually decreased with time. The pattern of PSA change was significantly different according to the risk groups (p = 0.011) with the slope of − 0.139, − 0.161 and − 0.253 ng/mL/month in low-, intermediate- and high-risk groups, respectively.ConclusionSBRT for localized prostate cancer showed favorable efficacy with minimal toxicities. The time to PSA nadir was significantly associated with treatment outcome. PSA revealed rapid initial decline and slower decrease with longer follow-up and the patterns of PSA changes were different according to the risk groups.

Early abiraterone acetate treatment is beneficial in Japanese castration-resistant prostate cancer after failure of primary combined androgen blockade.

BackgroundDevelopment of novel agents targeting the androgen axis has led to improved overall survival in castration-resistant prostate cancer (CRPC). This study aimed to investigate the optimal timing of treatment with one such agent, abiraterone acetate (AA), in Japanese patients.Materials and methodsBetween July 2014 and February 2016, 106 CRPC patients were administered AA in Nagoya City University Hospital, Nagoya, Japan and in four affiliated hospitals following failure of primary combined androgen blockade (CAB). Of these, records of 69 patients treated before chemotherapy were retrospectively analyzed. Patients were divided into two AA treatment groups: (1) first- or second-line after diagnosis of CRPC, designated the Early Group, and (2) third-line onwards, designated the Deferred Group. Prostate-specific antigen (PSA) response rate, ≥ 50% PSA decline rate with treatment, progression-free survival (PFS), and overall survival (OS) were compared between the two groups. National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 was used to classify adverse events.ResultsIn 24 patients in the Early Group and 45 patients in the Deferred Group, no significant differences in baseline parameters were observed between groups. PSA response rate, ≥ 50% PSA decline rate and PFS (but not OS) were significantly better in the Early Group than in the Deferred Group. Serum aspartate aminotransferase/alanine aminotransferase elevations were the most common Grade 3 treatment-related toxicities, and were clinically manageable. In subgroup analyses of the Early Group, comparison of first-line AA with second-line AA after flutamide treatment showed no changes in PSA response rate, PFS, or OS.ConclusionThis study suggests improved favorable outcomes of first- or second-line AA treatment in Japanese chemotherapy-naïve CRPC patients after failed CAB; statistical confirmation of such improvement was evident for PFS, but not OS. In addition, early AA treatment exhibited an acceptable safety profile.

Does Gleason pattern 5 influence the efficacy of enzalutamide against castration-resistant prostate cancer?

e598 Background: In this study, we evaluated our cohort treated with enzalutamide retrospectively. We focused on Gleason pattern 5 prostate cancer which was very aggressive cancer and we investigated the difference in efficacy of enzalutamide between the groups including Gleason pattern 5 or not, to understand if initial aggressiveness of prostate cancer influence the enzalutamide responses. Methods: A total of 190 CRPC cases treated with enzalutamide between June 2014 and July 2016 at our university and affiliated institutions were included in this study. We evaluated clinical and pathological factors, Prostate specific antigen(PSA) responses, and overall survival, retrospectively. Results: Of these, 80 cases did not have Gleason pattern 5 and 110 cases had Gleason pattern 5 (Gleason Score 4+5, 5+4 or 5+5). Initial PSA level was higher and metastasis was more frequent in Gleason pattern 5 group (p = 0.0328, and 0.0171, respectively). Docetaxel pretreatment, abiraterone pretreatment, PSA and other serological data at starting enzalutamide were not different between the groups other than steroidal use (p = 0.0441). Overall survival rate at 1 year and 2 years were 84.3% and 77.2% in Gleason pattern 5 negative cohort, and 81.2% and 63.5% in Gleason pattern 5 cohort (p = 0.2459). There were no differences in terms of PSA responses between these groups. Mean PSA decline rate (pattern 5 negative vs. positive) were 57.1% vs. 54.6% (p = 0.6555). ≥ 50% PSA decline rate were 62.5% vs. 60.9% (p = 0.8329), ≥ 90% decline rate were 28.75% vs. 28.2% (p = 0.9317). Conclusions: In this study, we concluded that aggressiveness of initial status did not influence the efficacy of enzalutamide treatment. And disease status might be almost same when introducing enzalutamide. Of course, we need to recognize that initial androgen deprivation therapy (ADT) could be more efficient for lower Gleeson pattern than higher Gleeson pattern. However there is possibility that aggressiveness of prostate cancer cell would change through ADT and/or chemotherapy. We should investigate how prostate cancer is changing and should evaluate the prostate cancer cell status before starting treatment to predict the efficacy and to decide the treatment agents.

Conventionally Fractionationed Volumetric Arc Therapy versus Hypofractionated Stereotactic Body Radiotherapy: Quality of Life, Side Effects, and Prostate-Specific Antigen Kinetics in Localized Prostate Cancer

ObjectivesTo compare conventionally fractionationed volumetric arc therapy (VMAT) and hypofractionated stereotactic body radiotherapy (SBRT) modalities in terms of prostate-specific antigen (PSA) kinetics, toxicity, and quality of life (QOL) in patients with localized prostate cancer. MethodsPatients received radical radiotherapy as either 33.5 Gy/5 fr for SBRT or 75.6 Gy/35 fr for VMAT. International Prostate Symptom Score (IPSS) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer Module (QLQ-PR25) forms were used to assess QOL. ResultsOf the 48 patients (28 in SBRT and 20 in VMAT) included in the study, 40 (20 in SBRT and 20 in VMAT) were evaluated for QOL status. PSA control rate was 100% and PSA nadir value was 0.5 ng/dl in both arms during the median follow-up period of 23 months. The magnitude of PSA bounce was higher in the SBRT arm than in the VMAT arm (P = 0.01). The PSA decline rate in the VMAT arm was higher than in the SBRT arm (P = 0.028). Three (10.7%) patients treated with SBRT who had a history of transurethral resection of the prostate (TURP) experienced grade 3 urinary toxicity. No significant difference was observed concerning sexual activity and sexual functioning scores, whereas scores at 10.5 and 13.5 months were decreased in both arms. The SBRT and VMAT arms had similar urinary incontinence, bowel symptoms, and IPSS obstruction scores. The magnitude of increase in IPSS scores at treatment completion was higher in the VMAT arm than in the SBRT arm (P = 0.046). The decrease in hormonal symptom scores at 4.5, 10.5, and 13.5 months was higher in the VMAT arm than in the SBRT arm (P = 0.007, 0.027, and 0.021, respectively). ConclusionsBoth treatment modalities had similar effectiveness and provided acceptable outcomes in terms of toxicity and QOL. Grade 3 urinary toxicities might be eliminated with careful patient selection for SBRT.

Prostate-specific antigen kinetics following hypofractionated stereotactic body radiotherapy versus conventionally fractionated external beam radiotherapy for low- and intermediate-risk prostate cancer.

The purpose of this study was to compare the prostate-specific antigen (PSA) kinetics between stereotactic body radiotherapy (SBRT) using Cyberknife and conventionally fractionated external beam radiotherapy (CF-EBRT) in low- and intermediate-risk prostate cancer. A total of 69 patients with low- and intermediate-risk prostate cancer were enrolled. Thirty-four patients were treated with SBRT (36.25 Gy in five fractions) using Cyberknife and 35 patients treated with CF-EBRT (70.2-75.6 Gy in 39-42 fractions). PSA nadir, rate of PSA decline and biochemical failure (BCF) free survival were calculated and compared. With a median follow-up of 53.6 months (range, 14-74), the median slopes for SBRT were -0.430, -0.199, -0.127 and -0.094 ng/mL/month, respectively, for durations of 1, 2, 3 and 4 years following radiotherapy. Similarly, for CF-EBRT, the median slopes were -0.529, -0.138, -0.109 and -0.056 ng/mL/month, respectively. The slope of CF-EBRT was significantly different with a greater median rate of change for 1 year than SBRT (P = 0.018). Conversely, the slopes of SBRT for duration for 2, 3 and 4 year tended to be continuously greater than CF-EBRT (P = 0.028, P = 0.058 and P = 0.128, respectively). The significantly lower PSA nadir was observed in SBRT (nadir 0.23 ng/mL) compared with CF-EBRT (nadir 0.37 ng/mL) (P = 0.011). Five-year BCF free survivals were 100% for SBRT and 80.8% for CF-EBRT (P = 0.031). Patients treated with SBRT experienced a lower PSA nadir and tended to a continuously greater rate of decline of PSA for duration 2, 3 and 4 years than CF-EBRT. The improved PSA kinetics of SBRT leaded to favorable BCF-free survival.

Prostate-specific antigen kinetics following hypofractionated stereotactic body radiotherapy boost and whole pelvic radiotherapy for intermediate- and high-risk prostate cancer.

Stereotactic body radiotherapy (SBRT) has emerged as an effective treatment for localized prostate cancer. However, prostate specific antigen (PSA) kinetics after SBRT has not been well characterized. The objective of the current study is to analyze the rate of PSA decline and PSA nadir following SBRT boost after whole pelvis radiotherapy (WPRT) in intermediate- and high-risk prostate cancer. From March 2008 to July 2014, 42 patients newly diagnosed, intermediate- and high-risk (NCCN definition) localized prostate cancer were treated with SBRT boost using Cyberknife after WPRT. The whole pelvis dose was 45 Gy (25 fractions of 1.8 Gy) and the SBRT boost dose was 21 Gy (3 fractions of 7 Gy). No one received androgen deprivation therapy (ADT) before biochemical relapse. PSA nadir and rate of change in PSA (slope) were calculated and compared. With a median follow-up of 53.6 months (range, 14-74), the median rates of decline of PSA were -0.605, -0.229 and -0.166 ng/mL/month, respectively, for durations of 1, 2 and 3 years postradiotherapy, respectively. The median PSA nadir was 0.32 ng/mL after a median 36 months. 4-year biochemical failure (BCF) free survival was 100 percent for intermediate-risk and 71.4 percent for high-risk patients (P = 0.002). In this report of intermediate- and high-risk prostate cancer, continuously greater rates of decline PSA for duration 1, 2 and 3 year following SBRT boost after WPRT resulted in lower PSA nadir. Also, SBRT boost after WBPT leads to favorable BCF-free survival.

Phase 1b Study of Abiraterone Acetate Plus Prednisone and Docetaxel in Patients with Metastatic Castration-resistant Prostate Cancer

Coadministration of docetaxel and abiraterone acetate plus prednisone (AA + P) may benefit patients with metastatic castration-resistant prostate cancer (mCRPC) because of complementary mechanisms of action. COU-AA-206 was a phase 1b study to determine the safe dose combination of docetaxel and AA + P in three cohorts of chemotherapy-naïve mCRPC patients. Twenty-two patients received escalating doses of docetaxel plus AA + P. The primary endpoint was the proportion of patients with a dose-limiting toxicity (DLT) between weeks 2 and 7. The recommended phase 2 dose (RP2D) was the highest safe combination of docetaxel plus AA + P. Prostate-specific antigen (PSA) changes and intensive pharmacokinetic parameters for each drug were evaluated. Docetaxel 75mg/m2 + AA 1000mg + P 10mg was deemed the RP2D, with DLT in one of six patients. PSA declines from baseline of ≥50% and ≥90% were observed for 85.7% and 66.7% of patients, respectively. During median follow-up of 14.5 mo, eight patients had PSA progression and six had radiographic progression or died. Systemic exposure was comparable for docetaxel and abiraterone when given alone or in combination. Studies are ongoing to confirm the efficacy of potent androgen receptor–targeted therapy plus taxane in early mCRPC. Patient summaryThe combination of hormonal therapy and chemotherapy may improve outcomes in men with metastatic prostate cancer. This study demonstrates the ability to combine the hormonal therapy agent abiraterone acetate, plus prednisone, and the chemotherapy drug docetaxel with an acceptable side effect profile. A high rate of prostate-specific antigen decline was seen, but the study was small and additional research is needed before this becomes a standard approach.

Prostate-specific antigen kinetics following hypofractionated stereotactic body radiotherapy for low- and intermediate-risk prostate cancer

Abstract Background Stereotactic body radiotherapy (SBRT) has emerged as an effective treatment for localized prostate cancer. However, prostate-specific antigen (PSA) kinetics after SBRT has not been well characterized. The objective of the current study is to analyze the rate of PSA decline and PSA nadir following hypofractonated SBRT in low- and intermediate-risk prostate cancer. Methods From 2008 to 2014, 36 patients newly diagnosed, low- and intermediate-risk (NCCN definition) prostate cancer were treated with SBRT using Cyberknife. Total dose of 36.25 Gy in 5 fractions of 7.25 Gy were administered. No one received androgen deprivation therapy (ADT). PSA nadir and rate of change in PSA (slope) were calculated and compared. Results With a median follow-up of 52 months (range, 13–71), the median rates of decline of PSA were −0.359, −0.199 and −0.127 ng/mL/month, respectively, for durations of 1, 2 and 3 years after radiotherapy, respectively. The decline of PSA was maximal in the first year and continuously decreased for durations of 2 and 3 year. The median PSA nadir was 0.27 ng/mL after a median 33 months. 5-year biochemical failure (BCF)-free survival was 100% for low- and intermediate-risk patients. Conclusions In this report of low- and intermediate-risk prostate cancer, continuous decrease of PSA level for duration 1, 2 and 3 year following SBRT using Cyberknife resulted in lower PSA nadir. Also, SBRT leaded to long-term favorable BCF-free survival in low- and intermediate-risk prostate cancer.

Prostate-specific antigen kinetics after primary stereotactic body radiation therapy using CyberKnife for localized prostate cancer.

PurposeTo assess prostate-specific antigen (PSA) kinetics and report on the oncologic outcomes for patients with localized prostate cancer treated with stereotactic body radiation therapy (SBRT) using CyberKnife.MethodsWe extracted the list and data of 39 patients with clinically localized prostate cancer who had undergone primary SBRT using CyberKnife between January 2008 and December 2012 from the Smart Prostate Cancer database system of Seoul St. Mary's Hospital. Changes in PSA over time, PSA velocity, and PSA nadir were evaluated from the completion of SBRT using CyberKnife. Biochemical recurrence (BCR)-free survival after primary SBRT using CyberKnife was determined using Kaplan–Meier analysis.ResultsThe rate of PSA decrease was maximal in the first month (median −3.34 ng/mL/mo), which then fell gradually with median values of −1.51, −0.32, −0.28, −0.20, and −0.03 ng/mL/mo for durations of 3, 6, 9, 12, and 24 months after SBRT using CyberKnife, respectively. The median PSA nadir was 0.31 ng/mL after a median 23 months. Kaplan–Meier analysis calculates an actuarial 5-year BCR-free survival after SBRT using CyberKnife as 80.8%.ConclusionsPSA decline occurred rapidly in the first month, and then the rate of PSA decline fell off steadily over time throughout 2 years after treatment. Also, SBRT using CyberKnife leads to long-term favorable BCR-free survival in localized prostate cancer.

Evaluation of treatment efficacy using a Bayesian mixture piecewise linear model of longitudinal biomarkers.

Prostate-specific antigen (PSA) is a widely used marker in clinical trials for patients with prostate cancer. We develop a mixture model to estimate longitudinal PSA trajectory in response to treatment. The model accommodates subjects responding and not responding to therapy through a mixture of two functions. A responder is described by a piecewise linear function, represented by an intercept, a PSA decline rate, a period of PSA decline, and a PSA rising rate; a nonresponder is described by an increasing linear function with an intercept and a PSA rising rate. Each trajectory is classified as a linear or a piecewise linear function with a certain probability, and the weighted average of these two functions sufficiently characterizes a variety of patterns of PSA trajectories. Furthermore, this mixture structure enables us to derive clinically useful endpoints such as a response rate and time-to-progression, as well as biologically meaningful endpoints such as a cancer cell killing fraction and tumor growth delay. We compare our model with the most commonly used dynamic model in the literature and show its advantages. Finally, we illustrate our approach using data from two multicenter prostate cancer trials. The R code used to produce the analyses reported in this paper is available on request.

Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862)

AbstractBACKGROUND:This phase 2 trial was designed to evaluate the efficacy of vorinostat in chemotherapy‐pretreated patients with metastatic castration‐resistant prostate cancer.METHODS:Patients with disease progression on 1 prior chemotherapy, a prostate‐specific antigen (PSA) ≥5 ng/mL, and adequate organ function were treated with 400 mg vorinostat orally daily. The primary endpoint was the 6‐month progression rate. Secondary endpoints included safety, rate of PSA decline, objective response, overall survival, and effects of vorinostat on serum interleukin‐6 (IL‐6) levels.RESULTS:Twenty‐seven eligible patients were accrued. The median number of cycles delivered was 2 (range, 1‐7). All patients were taken off therapy before 6 months. The best objective response in the eligible patient was stable disease in 2 (7%) patients. No PSA decline of ≥50% was observed. There was 1 grade 4 adverse event (AE), and 44% of patients experienced grade 3 adverse events. The most common adverse events were fatigue (81%), nausea (74%), anorexia (59%), vomiting (33%), diarrhea (33%), and weight loss (26%). Median time to progression and overall survival were 2.8 and 11.7 months, respectively. Median IL‐6 levels (pg/mL) were higher in patients removed from the protocol for toxicity compared with progression at all time points, including baseline (5.2 vs 2.1, P = .02), Day 15 Cycle 1 (9.5 vs 2.2, P = .01), Day 1 Cycle 2 (9.8 vs 2.2, P = .01), and end of study (11.0 vs 2.9, P = .09).CONCLUSIONS:Vorinostat at this dose was associated with significant toxicities limiting efficacy assessment in this patient population. The significant association between IL‐6 levels and removal from the study for toxicities warrants further investigation. Cancer 2009. © 2009 American Cancer Society.

PS1 Late breaking Immunotherapy (APC8015) for androgen independent prostate cancer (AIPC): final progression and survival data from a second Phase 3 trial

Coadministration of docetaxel and abiraterone acetate plus prednisone (AA + P) may benefit patients with metastatic castration-resistant prostate cancer (mCRPC) because of complementary mechanisms of action. COU-AA-206 was a phase 1b study to determine the safe dose combination of docetaxel and AA + P in three cohorts of chemotherapy-naïve mCRPC patients. Twenty-two patients received escalating doses of docetaxel plus AA + P. The primary endpoint was the proportion of patients with a dose-limiting toxicity (DLT) between weeks 2 and 7. The recommended phase 2 dose (RP2D) was the highest safe combination of docetaxel plus AA + P. Prostate-specific antigen (PSA) changes and intensive pharmacokinetic parameters for each drug were evaluated. Docetaxel 75 mg/m2 + AA 1000 mg + P 10 mg was deemed the RP2D, with DLT in one of six patients. PSA declines from baseline of ≥50% and ≥90% were observed for 85.7% and 66.7% of patients, respectively. During median follow-up of 14.5 mo, eight patients had PSA progression and six had radiographic progression or died. Systemic exposure was comparable for docetaxel and abiraterone when given alone or in combination. Studies are ongoing to confirm the efficacy of potent androgen receptor–targeted therapy plus taxane in early mCRPC.The combination of hormonal therapy and chemotherapy may improve outcomes in men with metastatic prostate cancer. This study demonstrates the ability to combine the hormonal therapy agent abiraterone acetate, plus prednisone, and the chemotherapy drug docetaxel with an acceptable side effect profile. A high rate of prostate-specific antigen decline was seen, but the study was small and additional research is needed before this becomes a standard approach.

Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer: Dahut WL, Gulley JL, Arlen PM, Liu Y, Fedenko KM, Steinberg SM, Wright JJ, Parnes H, Chen CC, Jones E, Parker CE, Linehan WM, Figg WD, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. J Clin Oncol 2004;22:2532–9

Both docetaxel and thalidomide have demonstrated activity in androgen-independent prostate cancer (AIPC). We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC. Seventy-five patients with chemotherapy-naive metastatic AIPC were randomly assigned to receive either docetaxel 30 mg/m2 intravenously every week for 3 consecutive weeks, followed by a 1-week rest period (n = 25); or docetaxel at the same dose and schedule, plus thalidomide 200 mg orally each day (n = 50). Prostate-specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decline, and time to progression. After a median potential follow-up time of 26.4 months, the proportion of patients with a greater than 50% decline in PSA was higher in the docetaxel/thalidomide group (53% in the combined group, 37% in docetaxel-alone arm). The median progression-free survival in the docetaxel group was 3.7 months and 5.9 months in the combined group (p = .32). At 18 months, overall survival in the docetaxel group was 42.9% and 68.2% in the combined group. Toxicities in both groups were manageable after administration of prophylactic low-molecular-weight heparin in the combination group. In this randomized phase II trial, the addition of thalidomide to docetaxel resulted in an encouraging PSA decline rate and overall median survival rate in patients with metastatic AIPC. After the prophylactic low-molecular-weight heparin was instituted to prevent venous thromboses, the combination regimen was well tolerated. Larger randomized trials are warranted to assess the impact of this combination.

Phase II Randomized Trial of Weekly Paclitaxel with or Without Estramustine Phosphate in Progressive, Metastatic, Hormone-Refractory Prostate Cancer

This study was conducted to determine the similarity of response rates and safety produced by weekly paclitaxel with or without oral estramustine in patients with metastatic hormone-refractory prostate cancer. Between December 1998 and December 1999, 163 patients were randomized to receive 28-day cycles of paclitaxel 100 mg/m2 on days 2, 9, and 16 plus estramustine 280 mg orally 3 times a day on days 1-3, 8-10, and 15- 17, or to receive paclitaxel 100 mg/m2 alone on days 1, 8, and 15. Objective response was defined as a ≥ 50% decrease in prostate-specific antigen (PSA) maintained for 4 weeks with stable or improved performance status. Response rates included 37 partial responses for paclitaxel/estramustine (47%) and 22 partial responses for paclitaxel (27%; P < 0.01). Median duration of response was 15.1 months for paclitaxel/estramustine and 15.5 months for paclitaxel; median survival was 16.1 months and 13.1 months, respectively (P = 0.049). Common toxicities for both treatments included neutropenia, gastrointestinal events, neuropathy, and asthenia. Thromboembolic events were more frequent in the paclitaxel/estramustine arm (no prophylactic anticoagulants). The rate of PSA decline for paclitaxel/estramustine was almost 2 times that of paclitaxel (47% vs. 27%), with acceptable toxicity. Multivariate analysis of prognostic factors affecting survival was not significant for treatment arm (P = 0.08). Although the incidence of thromboembolic events appeared to be increased in the paclitaxel/estramustine arm, the addition of estramustine was responsible for a 20% increase in the rate of PSA decline. Neither treatment arm had significant impact on quality of life as measured by the Functional Assessment of Cancer Therapy–Prostate quality of life questionnaire. This study produced encouraging data; further studies of paclitaxel/estramustine are recommended.

Modeling postradiation prostate specific antigen level kinetics

The goals of this study are twofold: 1) to describe the postradiation kinetics of nonrecurring prostate carcinoma based on prostate specific antigen (PSA) levels in men who remain biochemically free of disease; and 2) to determine predictors of all three components of the resulting piecewise exponential model based on pretreatment and treatment characteristics. Between March 1988 and May 1994, 153 patients with T1-T3 nonmetastatic prostate carcinoma were treated definitively with radiation therapy and at last follow-up had not failed biochemically (PSA rising on 2 consecutive occasions to a level > 1.0 ng/mL or 3 consecutive elevations). All patients were required to have at least 6 posttreatment PSA determinations and a minimum follow-up of 36 months. The median follow-up was 53 months (range, 36-94 months). A piecewise exponential model was used to describe the mean PSA levels because 1) the kinetics of postradiation PSA levels appear to follow first-order rate processes, and 2) there is evidence that PSA levels may rise slightly several years after treatment. Nonlinear mixed effects modeling was used in this situation because of the aforementioned nonlinearity and because variability between patients and within patients (PSA variation) must be taken into account. In addition, this methodology allows for modeling parameters as a function of patient and treatment characteristics. The random effects model based on the entire patient population demonstrated that PSA levels do not continue to drop 3 years after treatment, and that in fact the levels begin to rise slowly between 2-3 years after treatment. Pretreatment PSA was the only independent predictor of baseline PSA at time zero (end of radiation therapy). Gleason score was the only independent predictor of the rate of PSA decline after treatment, in which tumors with Gleason scores 7-10 drop at a slower rate than do tumors with Gleason scores 2-6. Finally, pretreatment prostate volume was the only independent predictor of the postnadir rise in PSA level, in which larger volumes translate to a steeper slope. The fact that pretreatment PSA level is the only independent predictor of the baseline PSA at time zero is not surprising. The observation that patients with tumors with higher Gleason scores have a slower rate of decline is in agreement with previous reports that these tumors contribute less PSA per unit volume than do tumors with moderate to well differentiation. Finally, the fact that no tumor-related characteristic (only pretreatment prostate volume) was predictive independently of the observed postnadir rise in PSA level suggests that these patients were cured.