Postradiation Prostate-specific Antigen Research Articles

Assessing radiation dose for postoperative radiotherapy in prostate cancer: Real world data.

BACKGROUNDApproximately 30% of patients with localized prostate cancer (PCa) who undergo radical prostatectomy will develop biochemical recurrence. In these patients, the only potentially curative treatment is postoperative radiotherapy (PORT) with or without hormone therapy. However, the optimal radiotherapy dose is unknown due to the limited data available. AIMTo determine whether the postoperative radiotherapy dose influences biochemical failure-free survival (BFFS) in patients with PCa. METHODSRetrospective analysis of patients who underwent radical prostatectomy for PCa followed by PORT-either adjuvant radiotherapy (ART) or salvage radiotherapy (SRT)-between April 2002 and July 2015. From 2002 to 2010, the prescribed radiation dose to the surgical bed was 66-70 Gy in fractions of 2 Gy; from 2010 until July 2015, the prescribed dose was 70-72 Gy. Patients were grouped into three categories according to the total dose administered: 66-68 Gy, 70 Gy, and 72 Gy. The primary endpoint was BFFS, defined as the post-radiotherapy prostate-specific antigen (PSA) nadir + 0.2 ng/mL. Secondary endpoints were overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS; based on conventional imaging tests). Treatment-related genitourinary (GU) and gastrointestinal (GI) toxicity was evaluated according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Finally, we aimed to identify potential prognostic factors. BFFS, OS, CSS, and MFS were calculated with the Kaplan-Meier method and the log-rank test. Univariate and multivariate Cox regression models were performed to explore between-group differences in survival outcome measures.RESULTSA total of 301 consecutive patients were included. Of these, 93 (33.6%) received ART and 186 (66.4%) SRT; 22 patients were excluded due to residual macroscopic disease or local recurrence in the surgical bed. In this subgroup (n = 93), 43 patients (46.2%) were Gleason score (GS) ≤ 6, 44 (47.3%) GS 7, and 6 (6.5%) GS ≥ 8; clinical stage was cT1 in 51 (54.8%), cT2 in 35 (39.3%), and cT3 in one patient (1.1%); PSA was < 10 ng/mL in 58 (63%) patients, 10-20 ng/mL in 28 (30.6%), and ≥ 20 ng/mL in 6 (6.4%) patients. No differences were found in BFFS in this patient subset versus the entire cohort of patients (P = 0.66). At a median follow-up of 113 months (range, 4-233), 5- and 10-year BFFS rates were 78.8% and 73.7%, respectively, with OS rates of 93.3% and 81.4%. The 5-year BFFS rates in three groups were as follows: 69.6% (66-68 Gy), 80.5% (70 Gy) and 82.6% (72 Gy) (P = 0.12):the corresponding 10-year rates were 63.9%, 72.9%, and 82.6% (P = 0.12), respectively. No significant between-group differences were observed in MFS, CSS, or OS. On the univariate analysis, the following variables were significantly associated with BFFS: PSA at diagnosis; clinical stage (cT1 vs cT2); GS at diagnosis; treatment indication (ART vs SRT); pre-RT PSA levels; and RT dose 66 -68 Gy vs. 72 Gy (HR: 2.05; 95%CI: 1.02-4.02, P = 0.04). On the multivariate analysis, the following variables remained significant: biopsy GS (HR: 2.85; 95%CI: 1.83-4.43, P < 0.001); clinical stage (HR: 2.31; 95%CI: 1.47-4.43, P = 0.01); and treatment indication (HR: 4.11; 95%CI: 2.06-8.17, P < 0.001). Acute grade (G) 1 GU toxicity was observed in 11 (20.4%), 17 (19.8%), and 3 (8.3%) patients in each group (66-68 Gy, 70 Gy and 72 Gy), respectively (P = 0.295). Acute G2 toxicity was observed in 2 (3.7%), 4 (4.7%) and 2 (5.6%) patients, respectively (P = 0.949). Acute G1 GI toxicity was observed in 16 (29.6%), 23 (26.7%) and 2 (5.6%) patients in each group, respectively (P = 0.011). Acute G2 GI toxicity was observed in 2 (3.7%), 6 (6.9%) and 1 (2.8%) patients, respectively (P = 0.278). No cases of acute G3 GI toxicity were observed.CONCLUSIONThe findings of this retrospective study suggest that postoperative radiotherapy dose intensification in PCa is not superior to conventional radiotherapy treatment.

Mechanistic modelling of prostate-specific antigen dynamics shows potential for personalized prediction of radiation therapy outcome.

External beam radiation therapy is a widespread treatment for prostate cancer. The ensuing patient follow-up is based on the evolution of the prostate-specific antigen (PSA). Serum levels of PSA decay due to the radiation-induced death of tumour cells and cancer recurrence usually manifest as a rising PSA. The current definition of biochemical relapse requires that PSA reaches nadir and starts increasing, which delays the use of further treatments. Also, these methods do not account for the post-radiation tumour dynamics that may contain early information on cancer recurrence. Here, we develop three mechanistic models of post-radiation PSA evolution. Our models render superior fits of PSA data in a patient cohort and provide a biological justification for the most common empirical formulation of PSA dynamics. We also found three model-based prognostic variables: the proliferation rate of the survival fraction, the ratio of radiation-induced cell death rate to the survival proliferation rate, and the time to PSA nadir since treatment termination. We argue that these markers may enable the early identification of biochemical relapse, which would permit physicians to subsequently adapt patient monitoring to optimize the detection and treatment of cancer recurrence.

Significance of prostate-specific antigen kinetics after three-dimensional conformal radiotherapy with androgen deprivation therapy in patients with localized prostate cancer.

To evaluate the relationship between biochemical recurrence and post-radiation prostate-specific antigen (PSA) kinetics in patients with localized prostate cancer treated by radiotherapy with various durations of androgen deprivation therapy (ADT). We reviewed our single-institution, retrospectively maintained data of 144 patients with T1c-T3N0M0 prostate cancer who underwent three-dimensional conformal radiotherapy (3D-CRT) between December 2005 and December 2015 and 113 patients were fulfilled the inclusion criteria. In this cohort, 3D-CRT was delivered with a dose in the range from 70.0 to 72.0Gy with ADT. All patients received ADT as concurrent regimens. Biochemical recurrence was defined on the basis of the following: "PSA nadir+2.0ng/ml or the clinical judgement of attending physicians". Kaplan-Meier, log-rank, and Cox regression analyses were carried out. The median follow-up period was 54.0months. The median duration of ADT was 17months (interquartile range, 10-24months). There was a trend toward statistical significant correlation between post-radiation PSA decline rate of≥90% and PSA recurrence (p=0.056). The same correlation could be observed in D'Amico high-risk patients (p=0.036). However, it was not observed between PSA nadir and PSA recurrence (p=0.40) in univariate analysis. Furthermore, multivariate analysis showed that post-radiation PSA decline rate of≥90% was a significant predictor of biochemical recurrence in patients who received radiotherapy with various durations of ADT (p=0.044). Post-radiation PSA decline rate of≥90% was a prognostic factor for biochemical recurrence in localized prostate cancer patients received 3D-CRT with various durations of ADT.

Prostate-Specific Antigen (PSA) Bounce After Dose-Escalated External Beam Radiation Therapy Is an Independent Predictor of PSA Recurrence, Metastasis, and Survival in Prostate Adenocarcinoma Patients

Toevaluate the difference in prostate-specific antigen (PSA) recurrence-free, distant metastasis-free, overall, and cancer-specific survival between PSA bounce (PSA-B) and non-bounce patients treated with dose-escalated external beam radiation therapy (DE-EBRT). During 1990-2010, 1898 prostate adenocarcinoma patients were treated with DE-EBRT to ≥75Gy with ≥5years follow-up. Patients receiving neoadjuvant/concurrent androgen-deprivation therapy (n=1035) or with fewer than 4 PSA values obtained 6months or more after post-EBRT completion (n=87) were excluded. The evaluable 776 patients were treated (median, 81.0Gy). Prostate-specific antigen bounce was defined as a ≥0.2-ng/mL increase above the interval PSA nadir, followed by a decrease to nadir or below. Prostate-specific antigen relapse was defined as post-radiation therapy PSA nadir + 2ng/mL. Median follow-up was 9.2years (interquartile range, 6.9-11.3years). One hundred twenty-three patients (15.9%) experienced PSA-B after DE-EBRT at a median of 24.6months (interquartile range, 16.1-38.5months). On multivariate analysis, younger age (P=.001), lower Gleason score (P=.0003), and higher radiation therapy dose (P=.0002) independently predicted PSA-B. Prostate-specific antigen bounce was independently associated with decreased risk for PSA relapse (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.33-0.85; P=.008), distant metastatic disease (HR 0.34; 95% CI 0.12-0.94; P=.04), and all-cause mortality (HR 0.53; 95% CI 0.29-0.96; P=.04) on multivariate Cox analysis. Because all 50 prostate cancer-specific deaths in patients without PSA-B were in the non-bounce cohort, competing-risks analysis was not applicable. A nonparametric competing-risks test demonstrated that patients with PSA-B had superior cancer-specific survival compared with patients without PSA-B (P=.004). Patients treated with dose-escalated radiation therapy for prostate adenocarcinoma who experience posttreatment PSA-B have improved PSA recurrence-free survival, distant metastasis-free survival, overall survival, and cancer-specific survival outcomes.

The use of 68 Ga-PSMA PET CT in men with biochemical recurrence after definitive treatment of acinar prostate cancer.

Early localisation of disease recurrence after definitive treatment of prostate cancer is vital to determine suitability for salvage treatment. Our aim was to further investigate the relationship between prostate specific antigen (PSA) level and detection of suspected cancer recurrence using 68 Ga-PSMA PET/CT in patients with biochemical recurrence after radical prostatectomy (RP) or radiotherapy, particularly at low PSA levels. This retrospective single tertiary referral institution cohort study of men reviewed the results of 68 Ga-PSMA PET/CT scans for investigation of post RP and post radiotherapy PSA recurrence following primary treatment of prostate cancer. We included men with suspected recurrent prostate cancer based on an elevated post treatment PSA level. The data collected analyzed the relationship of the pre-scan PSA level to the probability of a positive scan finding for recurrent prostate cancer. Of the cohort of 532 men, 425 had a previous RP and 107 had prior radiotherapy. The median PSA of the RP group was 0.59ng/mL and 5.8ng/mL in the radiotherapy group. In the post RP cohort, the detection rate of 68 Ga-PSMA PET/CT was 11.3% for PSA 0.01 to <0.2ng/mL, 26.6% for PSA 0.2 to <0.5ng/mL, 53.3% for PSA 0.5 to <1ng/mL, 79.1% for PSA 1 to <2ng/mL and 95.5% for PSA ≥2. Lymph node metastasis post RP was identified in 68% of men with suspected disease recurrence. In the post radiotherapy cohort the detection rate was 33.3% for PSA 0.01 to <0.5ng/mL, 71.4% for PSA 0.5 to <1ng/mL, 93.3% for PSA 1 to <2ng/mL and 100% for PSA ≥2. Local recurrence after radiotherapy was suspected in 71% of the cohort and 40% had suspected lymph node metastasis. To our knowledge, this is largest cohort study of detection rates of 68 Ga-PSMA PET/CT in patients with biochemical recurrence after definitive treatment of prostate cancer, including patients with PSA <0.5 and in a post radiotherapy cohort. Detection of suspected recurrent disease outside the pelvis at low PSA levels will influence the decision for salvage treatment options.

Natural History of Untreated Prostate Specific Antigen Radiorecurrent Prostate Cancer in Men with Favorable Prognostic Indicators

Background and Purpose. Life expectancy data could identify men with favorable post-radiation prostate-specific antigen (PSA) failure kinetics unlikely to require androgen deprivation therapy (ADT). Materials and Methods. Of 206 men with unfavorable-risk prostate cancer in a randomized trial of radiation versus radiation and ADT, 53 experienced a PSA failure and were followed without salvage ADT. Comorbidity, age and established prognostic factors were assessed for relationship to death using Cox regression analyses. Results. The median age at failure, interval to PSA failure, and PSA doubling time were 76.6 years (interquartile range [IQR]: 71.8–79.3), 49.1 months (IQR: 37.7–87.4), and 25 months (IQR: 13.1–42.8), respectively. After a median follow up of 4.0 years following PSA failure, 45% of men had died, none from prostate cancer and no one had developed metastases. Both increasing age at PSA failure (HR: 1.14; 95% CI: 1.03–1.25; P = 0.008) and the presence of moderate to severe comorbidity (HR: 12.5; 95% CI: 3.81–41.0; P < 0.001) were significantly associated with an increased risk of death. Conclusions. Men over the age of 76 with significant comorbidity and a PSA doubling time >2 years following post-radiation PSA failure appear to be good candidates for observation without ADT intervention.

Defining the Optimal Approach to the Patient With Postradiation Prostate-Specific Antigen Recurrence Using Outcome Data From a Prospective Randomized Trial

Following PSA failure, intermittent androgen suppression therapy (AST) has been shown to be non-inferior to continuous AST with respect to survival; however the optimal management remains unknown when considering comorbidity and PSA kinetics at recurrence. To define randomized clinical trials (RCT) to address this issue, we examine factors associated with the risk of death following PSA failure.

Age, comorbidity, and the risk of death in men with PSA failure following radiation therapy.

82 Background: Life expectancy data based on age and comorbidity may identify men with favorable post-radiation prostate-specific antigen (PSA) failure kinetics unlikely to experience metastasis despite withholding androgen deprivation therapy (ADT). Methods: Of 206 men with unfavorable-risk prostate cancer (PC) enrolled on a randomized trial of radiation vs. radiation + ADT, 108 had a PSA failure and 53 who did not receive slavage ADT because the PSA had not meet a pre-specified criteria of 10 ng/mL (n=41) or had significant comorbidity (n=12) and were followed with q1 year (yr) bone scan and q6 month (mo) PSA formed the study cohort. Comorbidity, age and established prognostic factors were evaluated with Cox regression to determine factors associated with death after PSA failure. Results: Median age at and interval to PSA failure and PSA doubling time were 76.6 yr (interquartile range [IQR] 71.8-79.3), 49.1 mo (IQR: 37.7 – 87.4), and 25 mo (IQR: 13.1 – 42.8) respectively. After a median follow up of 4.0 yr (IQR: 2.0 – 12.5) post PSA failure, 24 (45%) men died, none from PC and no one developed metastases. The median last follow up PSA was 3.6 ng/mL (IQR: 1.8 - 8.3). Increasing age at PSA failure (adjusted hazard ratio [AHR]: 1.14; 95% CI: 1.03 – 1.25; p=0.008) and the presence of moderate to severe comorbidity (AHR: 12.5; 95% CI: 3.81 – 41.0; p&lt;0.001) were significantly associated with an increased risk of death on multivariate analysis. At 4 yr, 86% above the median age at PSA failure and with moderate or severe comorbidity had died compared to 16% whose age was at the median or less and with no or minimal comorbidity (p&lt; 0.001). Conclusions: Men over age 76 with significant comorbidity and a PSA doubling time &gt; 2 yr following post-radiation PSA failure appear to be good candidates for surveillance. [Table: see text]

A 66-Year-old Man With Prostate-specific Antigen Recurrence and Lung Mass After Radical Prostatectomy

A67-year-old white male patient with a past medical history of prostate cancer status post nervesparing radical retropubic prostatectomy, malignant fibrohistiocytoma of the left hand, and basal cell carcinoma of the ear status post resection, presented for a follow-up visit to his urologist and was found to have an increased prostate-specific antigen (PSA). The patient had initially undergone a radical prostatectomy in December 1989 when he was 60 years old. Final pathology revealed a Gleason 6 adenocarcinoma with a focus of prostatic ductal carcinoma, organ confined (pT2) with negative margins (Figs. 1A, 1B). Initial postoperative PSA was undetectable, but in 1991, it became detectable and continued to increase to 0.8 in 1994. Bone scan and imaging of the pelvis were negative for metastatic disease. The patient received radiation therapy to his prostatic bed beginning July 1994 when the patient was 65 years old. His postradiation PSA was 0.8 and initially decreased, but in January 1997, it was 2.1. The patient denied any weight loss, fevers or chills, chest pain or shortness of breath, abdominal pain, bone pain, increased urinary frequency, urgency, or hesitancy, dysuria, or hematuria. He was having regular bowel movements. He was a lifetime nonsmoker. On examination, the patient was afebrile and his vital signs were stable. He was alert and generally appeared well. He had no cervical or axillary adenopathy. Lungs were clear to auscultation bilaterally. His abdomen was soft, nontender, and nondistended. He had a well-healed midline surgical scar. Rectal examination showed no palpable nodularity in the prostatic bed and good sphincter tone. Extremities were warm and well-perfused without edema, clubbing, or cyanosis. His laboratory test

Determinants of Change in Prostate-Specific Antigen Over Time and Its Association With Recurrence After External Beam Radiation Therapy for Prostate Cancer in Five Large Cohorts

To assess the relationship between prognostic factors, postradiation prostate-specific antigen (PSA) dynamics, and clinical failure after prostate cancer radiation therapy using contemporary statistical models. Data from 4,247 patients with 40,324 PSA measurements treated with external beam radiation monotherapy in five cohorts were analyzed. Temporal change of PSA after treatment completion was described by a specially developed linear mixed model that included standard prognostic factors. These factors, along with predicted PSA evolution, were incorporated into a Cox model to establish their predictive value for the risk of clinical recurrence over time. Consistent relationships were found across cohorts. The initial PSA decline after radiation therapy was associated with baseline PSA and T-stage (p < 0.001). The long-term PSA rise was associated with baseline PSA, T-stage, and Gleason score (p < 0.001). The risk of clinical recurrence increased with current level (p < 0.001) and current slope of PSA (p < 0.001). In a pooled analysis, higher doses of radiation were associated with a lower long-term PSA rise (p < 0.001) but not with the risk of recurrence after adjusting for PSA trajectory (p = 0.63). Conversely, after adjusting for other factors, increased age at diagnosis was not associated with long-term PSA rise (p = 0.85) but was directly associated with decreased risk of recurrence (p < 0.001). We conclude that a linear mixed model can be reliably used to construct typical patient PSA profiles after prostate cancer radiation therapy. Pretreatment factors along with PSA evolution and the associated risk of recurrence provide an efficient and quantitative way to assess the impact of risk factors on disease progression.

Time to Prostate-Specific Antigen Nadir After Androgen Suppression Therapy for Postoperative or Postradiation PSA Failure and Risk of Prostate Cancer-Specific Mortality

To examine whether the time to the prostate-specific antigen (PSA) nadir was associated with prostate cancer-specific mortality (PCSM) in men with PSA failure after radical prostatectomy or radiotherapy who do not achieve an undetectable PSA level (PSA level of 0.2 ng/mL or less) after 8 months of androgen suppression therapy (AST). The cohort included 162 men with localized prostate cancer treated with AST for an increasing PSA level after radical prostatectomy or radiotherapy. Gray's analysis was used to evaluate for an association between the time to PSA nadir after 8 months of AST and the time to PCSM, adjusting for established prognostic factors. The median age and follow-up after 8 months of AST was 71.2 and 1.8 years, respectively. After adjusting for Gleason score, pre-AST PSA doubling time, PSA at AST, PSA nadir value, time to PSA failure, initial treatment, and age, the time to PSA nadir was significantly associated with PCSM (adjusted hazard ratio 2.53, 95% confidence interval 1.24 to 5.14, P = 0.01). Men with a PSA nadir greater than the median value of 0.9 ng/mL and the time to PSA nadir longer than the median of 4 months had significantly greater PCSM estimates (P <0.001) compared with men with a PSA nadir of 0.9 ng/mL or less. The time to PSA nadir, combined with the PSA nadir level, can be used to identify men who are at high risk of PCSM after a short course of AST for entry onto clinical trials using novel systemic agents with AST.

Time to an undetectable prostate‐specific antigen (PSA) after androgen suppression therapy for postoperative or postradiation PSA recurrence and prostate cancer‐specific mortality

For men receiving androgen-suppression therapy (AST) for a rising postoperative or postradiation prostate-specific antigen (PSA) recurrence, whether the time to an undetectable (u) PSA was significantly associated with prostate cancer-specific mortality (PCSM) was evaluated. The study cohort comprised 585 men with a rising PSA and negative bone scan after surgery (n = 415) or radiation therapy (n = 170) that were treated with AST and achieved a uPSA. Gray's regression was used to evaluate whether the time to a uPSA after AST was significantly associated with the time to PCSM after the uPSA adjusting for known prognostic factors. The median time (interquartile range) to achieve a uPSA was 4.6 (range, 2.8-7.8) months. There were 23 deaths, 4 of which were from prostate cancer. An increasing time to a uPSA (adjusted hazard ratio [HR]: 9.2, 95% confidence interval [CI]: 3.8, 22.1; P < .0001), a decreasing PSA doubling time (DT) (HR: 0.58, 95% CI: 0.43, 0.80; P = .0007), and Gleason score 8 to 10 cancers (HR: 8.6, 95% CI: 1.04, 77; P = .05) were significantly associated with a shorter time to PCSM. Despite achieving a uPSA after AST, the risk of PCSM increased significantly as the time to the uPSA lengthens, especially in men with a short pre-AST PSA DT and high-grade prostate cancer. These men should be considered for randomized studies evaluating immediate vs delayed chemotherapy after the achievement of the uPSA.

Evaluation of postradiotherapy PSA patterns and correlation with 10-year disease free survival outcomes for prostate cancer

To describe the prostate-specific antigen (PSA) pattern profiles observed after external beam radiotherapy with and without short-term neoadjuvant androgen deprivation therapy (ST-ADT) and to report the association of established posttreatment PSA patterns with long-term disease-free survival outcomes. A total of 1,665 patients were treated with conformal external beam radiotherapy for clinically localized prostate cancer. Of 570 patients who had the requisite>10 consecutive PSA measurements for statistical analysis, 194 patients received a median of 3 months of ADT before radiotherapy and 376 were treated with radiotherapy alone. The median follow up was 103 months. In the group treated with ST-ADT, three distinct postradiotherapy PSA patterns were identified: a stable trend (44%), an increasing trend followed by stabilization of the PSA (25%), and an increasing trend (31%). Among the subgroup that demonstrated a rising and subsequent stabilizing patterns, PSA levels had gradually risen to a median value of 0.9 ng/mL after therapy, stabilized, and remained durably suppressed. The only identified trends among patients treated with external beam radiotherapy without ST-ADT were declining PSA levels followed by stable PSA trends or declining patterns followed by rising levels. Patients whose PSA levels stabilized after an initial rise or those with slowly rising PSA profiles had a lower incidence of distant metastasis compared to those with accelerated rises after therapy. For those treated with external beam radiotherapy in conjunction with ST-ADT, a significant percentage who develop a rising PSA after treatment are expected to manifest subsequent stabilization at plateaued levels of approximately 1.0 ng/mL, which can remain durably suppressed. The likelihood of distant metastasis in these patients is low despite the PSA stabilization at levels 1.0 ng/mL or higher and comparable to outcomes observed for those with lower nonrising PSA values.

Prostate-Specific Antigen Nadir and Cancer-Specific Mortality Following Hormonal Therapy for Prostate-Specific Antigen Failure

For men receiving androgen-suppression therapy (AST) for a rising postoperative or postradiation prostate-specific antigen (PSA), we evaluated whether a PSA nadir of more than 0.2 ng/mL was significantly associated with prostate cancer-specific mortality (PCSM). The study cohort comprised 747 men with rising PSA and negative bone scan after surgery (n = 486) or radiation therapy (n = 261) who were treated with AST. Cox regression was used to evaluate whether a significant association existed between the PSA nadir level after 8 months of AST and the time to PCSM, controlling for treatment and known prognostic factors. The post-AST PSA nadir (pCox < .0001), the pre-AST PSA doubling time (DT) (pCox = .002), PSA level (P = .0001), and Gleason eight to 10 cancers (pCox = .01) were significantly associated with time to PCSM. The adjusted hazard ratio for PCSM was 20 (95% CI, 7 to 61; pCox < .0001), for men with a PSA nadir of more than 0.2 ng/mL as compared with all others. A PSA DT of less than 3 months was observed in 30% (224 of 747) of the study cohort. Of the 28 observed prostate cancer deaths, 21 (75%) occurred in men whose PSA nadir was more than 0.2 ng/mL and who had a PSA DT of less than 3 months. A PSA nadir of more than 0.2 ng/mL after 8 months of AST given for postoperative or postradiation PSA failure is significantly associated with PCSM and is clinically significant because it accounted for 75% of the cancer deaths observed in this study.

The clinical significance of a PSA nadir &gt; 0.2 to patients with a rising post-operative or post-radiation PSA treated with androgen deprivation

4547 Purpose: For men receiving androgen deprivation therapy (ADT) for a rising post-operative or post-radiation prostate-specific antigen (PSA) state, we evaluated whether a PSA nadir level of > 0.2 ng/ml as compared to 0.2 ng/ml or less was significantly associated with prostate cancer-specific mortality (PCSM). Patients and Methods: The study cohort comprised 747 men with a rising PSA and negative bone scan following surgery (N = 486) or radiation therapy (N = 261) that were treated with ADT and followed for a median of 2.2 (0.8 - 9.5) years following PSA nadir. Cox regression was used to evaluate whether a significant association existed between the PSA nadir level and the time to PCSM following PSA nadir controlling for treatment and known prognostic factors. Results: The post-ADT PSA nadir (pCox < 0.0001), the pre-ADT PSA DT (pCox = 0.002), and Gleason 8 to 10 cancers (pCox = 0.01) were significantly associated with time to PCSM; whereas initial local therapy (pCox = 0.19), interval to PSA failure (pCox = 0.20), Gleason score 7 cancer (pCox = 0.17) were not. The adjusted hazard ratio for PCSM was 20 [95% Confidence Interval (CI): 7, 61; pCox < 0.0001] for men with a PSA nadir of > 0.2 ng/ml as compared to all others. A PSA DT < 3 months was observed in 30% (224/747) of the study cohort. Of the 28 observed prostate cancer deaths, 21 (75%) and 3 (11%) occurred in men whose PSA nadir was > 0.2 ng/ml and who had a PSA DT < 3 months or between 3 and 8.99 months respectively as shown in the Table. Conclusion: A PSA nadir > 0.2 ng/ml following ADT given for a post-operative or post-radiation PSA DT < 3 months is closely associated with PCSM and clinically significant because it accounted for nearly all of the cancer death observed in this study. No significant financial relationships to disclose.

Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy: Stephenson AJ, Shariat SF, Zelefsky MJ, Kattan MW, Butler EB, Teh, BS, Klein EA, Kupelian PA, Roehrborn CG, Pistenmaa DA, Pacholke HD, Liauw SL, Katz, MS, Leibel SA, Scardino PT, Slawin KM, Department of Urology, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY. JAMA

Salvage radiotherapy may potentially cure patients with disease recurrence after radical prostatectomy, but previous evidence has suggested that it is ineffective in patients at the highest risk of metastatic disease progression. To delineate patients who may benefit from salvage radiotherapy for prostate cancer recurrence by identifying variables associated with a durable response. Retrospective review of a cohort of 501 patients at 5 US academic tertiary referral centers who received salvage radiotherapy between June 1987 and November 2002 for detectable and increasing prostate-specific antigen (PSA) levels after radical prostatectomy. Disease progression after salvage radiotherapy, defined as a serum PSA value ⩾0.1 ng/mL above the postradiotherapy PSA nadir confirmed by a second PSA measurement that was higher than the first by any amount, by a continued increase in PSA level after treatment, or by the initiation of androgen deprivation therapy after treatment. Over a median follow-up of 45 months, 250 patients (50%) experienced disease progression after treatment, 49 (10%) developed distant metastases, 20 (4%) died from prostate cancer, and 21 (4%) died from other or unknown causes. The 4-year progression-free probability (PFP) was 45% (95% confidence interval [CI], 40%–50%). By multivariable analysis, predictors of progression were Gleason score of 8 to 10 (hazard ratio [HR], 2.6; 95% CI, 1.7–4.1; P < .001), preradiotherapy PSA level greater than 2.0 ng/mL (HR, 2.3; 95% CI, 1.7–3.2; P < .001), negative surgical margins (HR, 1.9; 95% CI, 1.4–2.5; P < .001), PSA doubling time (PSADT) of 10 months or less (HR, 1.7; 95% CI, 1.2–2.2; P = .001), and seminal vesicle invasion (HR, 1.4; 95% CI, 1.1–1.9; P = .02). Patients with no adverse features had a 4-year PFP of 77% (95% CI, 64%–91%). When treatment was given for early recurrence (PSA level ⩽2.0 ng/mL), patients with Gleason scores of 4 to 7 and a rapid PSADT had a 4-year PFP of 64% (95% CI, 51%–76%) and of 22% (95% CI, 6%–38%) when the surgical margins were positive and negative, respectively. Patients with Gleason scores of 8 to 10, positive margins, and receiving early salvage radiotherapy had a 4-year PFP of 81% (95% CI, 57%–100%) when the PSADT was longer than 10 months and of 37% (95% CI, 16%–58%) when the PSADT was 10 months or less. Gleason score, preradiotherapy PSA level, surgical margins, PSADT, and seminal vesicle invasion are prognostic variables for a durable response to salvage radiotherapy. Selected patients with high-grade disease and/or a rapid PSADT who were previously thought to be destined to develop progressive metastatic disease may achieve a durable response to salvage radiotherapy.

Perineural invasion is associated with increased relapse after external beam radiotherapy for men with low-risk prostate cancer and may be a marker for occult, high-grade cancer

Purpose To investigate the risk of postradiotherapy prostate-specific antigen (PSA) failure on the basis of pretreatment risk factors in prostate cancer patients with and without perineural invasion (PNI) in prostate biopsy specimens and to explain the observation that otherwise low-risk patients with PNI experience decreased freedom from PSA failure after external beam radiotherapy (RT). Methods and materials The study cohort consisted of 381 patients who underwent RT between 1989 and 2000 for clinically localized prostate cancer. A single genitourinary pathologist scored the absence or presence of PNI on all prostate biopsy specimens. Patients were divided into low-, intermediate- and high-risk subgroups on the basis of their 1992 American Joint Committee on Cancer T-stage, pretreatment PSA level, and Gleason score. Cox regression uni- and multivariate analyses were performed to evaluate whether the presence or absence of PNI in the biopsy specimen was a predictor of the time to post-RT PSA failure for patients in each pretreatment risk group. PSA failure was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. Actuarial PSA failure-free survival was estimated using the Kaplan-Meier method, and comparisons were performed using the log–rank test. Results Cox regression univariate analysis revealed that PNI was a significant predictor of the time to PSA failure in the low-risk ( p = 0.04) and high-risk ( p = 0.03) cohorts. The 5-year PSA failure-free survival rate was 50% vs. 80% ( p = 0.04) in low-risk patients, 70% vs. 75% ( p = 0.72) in intermediate-risk patients, and 29% vs. 53% ( p = 0.03) in high-risk patients with and without PNI, respectively. Cox regression multivariate analysis within the high-risk group revealed that a PSA level ≥20 ng/mL ( p = 0.01) and Gleason score ≥8 ( p = 0.02), but not PNI, were the only significant predictors of the time to PSA failure after RT. However, an association was found between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 8–10 ( p = 0.06). The association was stronger between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 7–10 ( p = 0. 033). Conclusion A decrement in PSA outcome after RT for low-risk patients with PNI-positive biopsy specimens was found. The association between PNI and high Gleason score provides a possible explanation for the loss of statistical significance of PNI in the Cox regression multivariate analysis of the high-risk cohort. The data suggest that PNI found in the biopsy specimen of an otherwise low-risk patient predicts for occult high-grade disease that is missed owing to the sampling error associated with prostate biopsy. The association between PNI and a high Gleason score argues for the use of more aggressive therapy, such as hormonal therapy with RT and/or dose escalation, in these select patients.

Prostate Specific Antigen Bounce After Simultaneous Irradiation for Prostate Cancer: The Relationship to Patient Age

We report on the relationship of patient age to prostate specific antigen (PSA) bounce after brachytherapy for prostate cancer. From 1992 to 1997, 1,011 consecutive men with stage T1-T2NxM0 prostate cancer were treated with simultaneous irradiation, transperineal prostate I-125 implant followed by external beam irradiation. No patients received neoadjuvant hormones. There were 251, 491 and 269 men 60 years old or younger, 61 to 70 and 71 or older, respectively, at implant. PSA bounce is defined by a postirradiation PSA increase of 0.1 ng/ml or more above the level before bounce followed by a decrease to or below that level. Disease freedom is defined by a PSA cut point of 0.2 ng/ml. Median followup is 6 years (range 3 months to 10 years). The frequency of PSA bounce according to age 60 or younger, 61 to 70 and 71 or older is 57%, 41% and 26%, respectively, a significant difference (p <0.000), average time to bounce onset is 19, 20 and 25 months for these 3 age groups, respectively, a significant difference (p = 0.002), and average bounce duration is 11, 8 and 8 months, respectively, a significant difference (p <0.000). On multivariate analysis of age, pretreatment PSA, Gleason score, stage, implant dose, prostate volume, diabetes and race, only age is significantly associated with PSA bounce (p <0.0001). After adjusting for the inherent bias caused by PSA bounce, there is no significant difference in disease-free survival between men with and without bounce. Young men with prostate cancer treated with brachytherapy have a significantly higher frequency, earlier onset and longer duration of PSA bounce than older men.

Correlation between Doppler Vascular Density and PSA Response to Radiation Therapy in Patients with Localized Prostate Carcinoma

Rationale and Objectives The authors performed this study to ascertain whether there is a correlation between pretreatment Doppler vascular density (DVD) of the prostate and prostate-specific antigen (PSA) response following radiation therapy in prostate cancer patients. Materials and Methods Prior to radiation therapy, 14 patients with biopsy-proven carcinoma (of Gleason grades 2–7) were imaged with transrectal ultrasound in gray-scale, color Doppler, and power Doppler modes. The Doppler images were analyzed for mean DVD with the aid of a computer program. PSA levels were measured before therapy and every 3 months after therapy. The PSA measurements were fitted to an exponential to determine PSA halving time ( T 1/2). Correlations were made between T 1/2> and the following pretherapy measurements: mean DVD, PSA level, prostate volume, and Gleason grade. Results Median follow-up time was 392 days. A linear correlation with regression coefficient ( R) of 0.75–0.80 was observed between mean DVD and T 1/2> for color Doppler and power Doppler imaging. In both imaging modes, each percentage increase in mean DVD led to an increase in T 1/2> by 25 days. Pretherapy prostate volume, PSA level, and Gleason score did not correlate with T 1/2>. Conclusion The pretreatment mean DVD correlates inversely with the rate of posttherapy decline in PSA in patients with prostate cancer. That is, pretreatment vascularity prognosticates postirradiation PSA response. The mechanism underlying this correlative relationship is not known.

Radiation Therapy for Increasing Prostate-Specific Antigen Levels After Radical Prostatectomy

Herein we present data on outcomes in patients with increasing prostate-specific antigen (PSA) levels treated with irradiation to the pelvis and/or prostatic bed after radical prostatectomy. Between 1988 and 1998, 92 patients who presented with increasing PSA levels after radical prostatectomy were treated with irradiation, 29 to the pelvis and prostatic bed and 63 to the prostatic bed only. The mean follow-up was 4 years for the 3D-CRT group and 6.5 years for the standard radiation therapy group. Criterion for biochemical failure was an increase in post irradiation PSA level on ≥ 1 consecutive measurement. Patients were classified into 3 risk groups based on prognostic factors: pathologic tumor extent and stage, Gleason score, and PSA levels before irradiation. Acute and late morbidity was quantitatively evaluated in all patients. There was a close correlation between the preirradiation PSA level and the probability of 4-year biochemical failure–free survival (75% with PSA levels ≥ 1 ng/mL, 30% with PSA levels of 1.1-2 ng/mL, and 20% with PSA levels > 2 ng/mL; P = 0.05). The 4-year chemical failure rate was 20% in the low/intermediate-risk group and 65% in the high-risk group (P = 0.36). In 20 patients in the low-PSA group (≥ 1 ng/mL) receiving doses > 62 Gy, no biochemical failures have been detected in comparison to a 70% failure rate at 4 years in patients treated with lower doses (P = 0.15). In the higher-PSA groups, no impact of irradiation dose on outcome was noted (40%–60% incidence of failure at 3 years). Pelvic irradiation was associated with a trend toward decreased biochemical failure rate in the low-PSA group (70% vs. 0% at 4 years; P = 0.35), but not in the high-PSA group. Only 1 patient (1.5%) experienced clinical local recurrence in the prostatic bed and 2 patients (1.8%) had distant metastases. Treatment has been very well tolerated, with only 3 patients in the arc-rotation group experiencing grade 2 treatment toxicity. Prostate bed irradiation is an effective treatment in a significant proportion of patients who present with a biochemical failure after radical prostatectomy.