Posttreatment Prostate-specific Antigen Values Research Articles

Prostate-Specific Antigen Bounce After Dose-Escalated Radiation Therapy for Prostate Cancer is an Independent Predictor for Distant Metastasis, Cancer-Specific Survival, and Overall Survival

Prostate-Specific Antigen Bounce After Dose-Escalated Radiation Therapy for Prostate Cancer is an Independent Predictor for Distant Metastasis, Cancer-Specific Survival, and Overall Survival

Postradiotherapy 2-Year Prostate-Specific Antigen Nadir as a Predictor of Long-Term Prostate Cancer Mortality

To report the influence of posttreatment prostate-specific antigen (PSA) nadir response at 2 years after external beam radiotherapy (RT) on distant metastases (DM) and cause-specific mortality (CSM). Eight hundred forty-four patients with localized prostate cancer were treated with conformal RT. The median duration of follow-up was 9.1 years. A fixed landmark time point at 2 years was used to assess the influence of nadir PSA value as a time-dependent variable on long-term outcomes. Multivariate analysis demonstrated that nadir PSA <or=1.5 ng/mL at the landmark was an independent predictor of progression-free survival after adjusting for T stage, Gleason score, pre-RT PSA value, and RT dose (p = 0.03). The 5- and 10-year cumulative incidences of DM were 2.4% and 7.9%, respectively, in those with nadir PSA levels <or=1.5 ng/mL at the 2-year landmark, and were 10.3% and 17.5%, respectively, in patients with higher nadir values. Multivariate analysis showed that the higher nadir PSA value at the 2-year landmark (p = 0.002), higher Gleason scores (p < 0.001), and increasing T stage (p = 0.03) were predictors of DM after adjusting for pre-RT PSA values and RT dose. Multivariate analysis also showed that higher Gleason scores (p = 0.002), and higher nadir PSA values at the 2-year landmark (p = 0.03) were risk factors associated with CSM after adjusting for T stage and pre-RT PSA value. Nadir PSA values of <or=1.5 ng/mL at 2 years after RT for prostate cancer predict for long-term DM and CSM outcomes. Patients with higher absolute nadir levels at 2 years after treatment should be evaluated for the presence of nonresponding disease, and earlier salvage treatment interventions should be considered.

Improved biochemical relapse-free survival for patients with large/wide glands treated with prostate seed implantation for localized adenocarcinoma of prostate

Objectives To analyze whether prostate size affects biochemical relapse-free survival (bRFS). Methods The bRFS outcomes for 390 patients with a minimum of 2 years of follow-up were determined from a review of a prospectively maintained database. All patients were treated with iodine-125 alone as the radiotherapeutic modality and had a minimum of four posttreatment prostate-specific antigen values. None were treated with androgen deprivation. The factors examined in the univariate and multivariate analyses predicting for bRFS included gland volume, patient age, initial prostate-specific antigen value, biopsy Gleason score, clinical stage, and postimplant dosimetric variables. Results Most patients had low-risk disease, and the median follow-up was 45 months (range 24 to 102). Using the American Society for Therapeutic Radiology Oncology definition of biochemical failure, the overall 5-year bRFS rate was 89.3%. On separate multivariate analyses, only the pretreatment prostate width and volume significantly influenced bRFS favorably ( P = 0.0069 and P = 0.0255, respectively). No association was found between gland size/width and postimplant dosimetry. Conclusions The results of our study have shown that implantation of large/wide prostates independently confers better bRFS.

Biochemical failure and the temporal kinetics of prostate-specific antigen after radiation therapy with androgen deprivation

The accuracy of the American Society of Therapeutic Radiation Oncology consensus definition of biochemical failure (BF) after radiation therapy (RT) and androgen deprivation (AD) has been questioned, because posttreatment prostate-specific antigen (PSA) levels typically rise after release from AD, and misclassification of BF may be made. The temporal kinetics of posttreatment PSA levels was examined to define the error in the classification of BF. Between December 1, 1991 and April 30, 1998, 688 men with T1c-T3 NX/0 M0 prostate cancer received three-dimensional conformal RT alone (n = 586) or in combination with either short-term (STAD: 3 to 12 months, n = 82) or long-term (LTAD: 12 to 36 months, n = 20) AD. Follow-up, calculated from the end of all treatment, was >/=48 months. The mean posttreatment PSA was calculated in 3-month intervals. The median posttreatment clinical follow-up period was 76 months (range, 48-152 months). The posttreatment PSA values from the end of all treatment for the RT+STAD-BF group showed an initial period of rise followed by a period of decline at 30 months and then a continued rise again. The decline in the mean posttreatment PSA is explained in part by stabilization in PSA level after 3 consecutive rises. Nonbiochemical failures (NBF) after RT+STAD had a relatively constant mean PSA over time of approximately 0.5 ng/mL. Unlike the RT+STAD-NBF profile, the RT+LTAD-NBF profile rose continuously and steadily to a level approaching 1 ng/mL. The RT+LTAD-BF profile rose continuously but at a slower rate over time. Nine RT+STAD-NBF patients (22%) and 2 RT+LTAD-BF (29%) patients experienced 3 consecutive rises followed by a subsequent decline and stabilization of PSA compared to 10 RT-BF patients (5%). Redistributing these misclassified patients to their respective NBF groups changed the mean posttreatment PSA profiles as follows: The RT+LTAD-BF profile rose constantly and steadily with a doubling time of approximately 16 months, and the RT+LAD-NF initially rose to a value of approximately 0.5 ng/mL, then at 36 months began to decline. The temporal kinetics of posttreatment PSA after RT+AD and RT alone are different. The American Society of Therapeutic Radiation Oncology definition for biochemical failure overestimates BF in 20-30% after RT+AD compared to 5% after RT alone.

A reduction in the rate of PSA rise following chemotherapy in patients with metastatic hormone refractory prostate cancer (HRPC) predicts survival: Results of a pooled analysis of CALGB HRPC trials

4506 Background: A prostate-specific antigen (PSA) decline of > 50% is associated with a prolongation in survival for patients with metastatic hormone refractory prostate cancer (HRPC). However, whether any reduction in the rate of PSA rise following chemotherapy prolongs survival remains unanswered. Methods: Four pooled multi-institutional Cancer and Leukemia Group B randomized phase III trials containing a minimum of 3 pre-treatment and 3 post-treatment PSA values, and follow up information on 153 men with metastatic HRPC who received chemotherapy for progressive metastatic HRPC formed the study cohort. The ability of the ratio (R) of the post to pre-chemotherapy PSA slope and its constituents to predict time to death following chemotherapy was assessed using the proportional hazards regression model. Results: At the time of this analysis, 139 men had died. When evaluated by tertiles, R was associated (pCox ≤ 0.09) with time to death following chemotherapy controlling for the value of the pre-chemotherapy PSA slope (pCox = 0.02). The median survival following chemotherapy for patients whose R-value was in the best (< - 0.8), middle (- 0.8 or more and up to - 0.3) or worse response tertile (> - 0.3) was 25 months [95% Confidence Interval (CI): 19–30], 23 months [95% CI: 18–29], and 18 months [95% CI: 14–23] respectively. The adjusted Hazard Ratio for death was 0.7 [95% CI: 0.45–1.05; pCox = 0.09] and 0.7 [95% CI: 0.45–1.04; pCox = 0.08] for patients with an R-value in the best and middle response tertile respectively as compared to the worse response tertile. Conclusion: A reduction in the rate of PSA rise following chemotherapy is associated with a prolongation in survival. Therefore, R may be an intermediate end point for mortality in patients with metastatic HRPC. Prospective validation is warranted. No significant financial relationships to disclose.

Individualized Predictions of Disease Progression Following Radiation Therapy for Prostate Cancer

Following treatment for localized prostate cancer, men are monitored with serial prostate-specific antigen (PSA) measurements. Refining the predictive value of post-treatment PSA determinations may add to clinical management, and we have developed a model that predicts future PSA values and the time to future clinical recurrence for individual patients. Data from 934 patients treated between 1987 and 2000 were used to develop a comprehensive statistical model to fit the clinical recurrence events and patterns of PSA data. A logistic model was used for the probability of cure, mixed models were used for serial PSA measurements, and a proportional hazards model was used for recurrences. Data available through February 2001 were fit to the model, and data collected between February 2001 and September 2003 were used for validation. T-stage, baseline PSA, and radiotherapy dosage are all associated with probability of cure. The risk of clinical recurrence in those not cured is strongly affected by the slope of PSA values. We show how the model can be used for individual monitoring of disease progression. For each patient the model predicts, based on baseline characteristics and all post-treatment PSA values, the probability of future clinical recurrences and future PSA values. The model accurately predicts risk of recurrence and future PSA values in the validation data set. This predictive information on future PSA values and the risk of clinical relapse for each individual patient, which can be updated with each additional PSA value, may prove useful to patients and physicians in determining post-treatment salvage strategies.

Radiotherapy Options for Localized Prostate Cancer Based Upon Pretreatment Serum Prostate-Specific Antigen Levels and Biochemical Control: A Comprehensive Review of the Literature

Purpose: To review all the available radiotherapy (RT) literature on localized prostate cancer treatment where serum prostate-specific antigen (PSA) levels were used to both stratify patients and evaluate outcome and determine if any conclusions can be reached regarding an optimal radiotherapeutic management for this disease. Methods and Materials: A MEDLINE search was conducted to obtain all articles in English on prostate cancer treatment employing RT from 1986–1997. Studies were considered eligible for review only if they met all the following criteria: 1) pretreatment PSA values were recorded and grouped for subsequent evaluation, 2) posttreatment PSA values were continuously monitored, 3) definitions of biochemical control were stated, and 4) the median follow-up was given. Results: Of the 246 articles identified, only 20 met the inclusion criteria; 4 using conformal external beam RT, 8 using conventional external beam RT, and 8 using interstitial brachytherapy (4 using a permanent implant alone, 3 combining external beam RT with a permanent implant, and 1 combining a conformal temporary interstitial implant boost with external beam RT). No studies using neutrons (with or without external beam RT) or androgen deprivation (combined with external beam RT) were identified where patients were stratified by pretreatment PSA levels. Results for all therapies were extremely variable with the 3–5-year rates of biochemical control for patients with pretreatment PSA levels ≤4 ng/ml ranging from 48 to 100%, for PSA levels >4 and ≤10 ng/ml ranging from 44 to 90%, for PSA levels >10 and ≤20 ng/ml ranging from 27 to 89%, and for PSA levels >20 ranging from 14 to 89%. The median Gleason score, T-stage, definition of biochemical control, and follow-up were substantially different from series to series. No RT option consistently produced superior results. Conclusions: When data are reviewed from studies using serum PSA levels to stratify patients and to evaluate treatment outcome, no consistently superior RT technique was identified. These data suggest that standard definitions of disease stage (combining clinical, pathologic, and biochemical criteria) and a common definition of biochemical cure (as developed by the American Society for Therapeutic Radiology and Oncology Consensus Panel) need to be adopted to evaluate treatment efficacy and advise patients on the most appropriate radiotherapeutic option for their disease.

Optimization of conformal radiation treatment of prostate cancer: Report of a dose escalation study

Purpose : The development of conformal radiation technique including improved patient immobilization has allowed us to test the value of dose escalation in optimizing the radiation treatment of prostate cancer. Methods and Materials : Outcome is reported for 233 consecutive patients treated with conformal technique between March 1989 and October 1992. Dose was escalated from 68 Gy to 79 Gy. Patient status is reported at 3 years follow-up, which is available in all alive patients. Pretreatment and serial posttreatment prostate specific antigen (PSA) values are available for all patients. Pretreatment and serial post >1.5 ngm/ml and rising on two consecutive measures. Dose response for bNED control of cancer and late morbidity are represented by logit response models fitted to the data. Kaplan-Meier methods, the log rank test, and Cox Regression models are also used. Results : No dose response is observed for bNED survival for patients with pretreatment PSA <10 ngm/ml comparing patients treated above or below 71.5 Gy or on multivariate analysis. Dose response is observed for bNED survival for pretreatment PSA groups of 10–19.9 ngm/ml. The dose associated with 50% bNED survival at 3 years is 64 Gy and 76 Gy, respectively. The slope of the dose responses are 13 and 9%, respectively. Dose response is demonstrated for Grade 2 gastrointestinal (GI), Grade 2 genitourinary (GU), and Grade 3,4 combined GI and GU late morbidity. The slopes of the morbidity resposnes are steeper than for cancer control (19 to 21%). Conclusions : Patients with pretreatment PSA <10 nmg/ml do not benefit from dose escalation, and the serious late morbidity of conformal radiation at 70 Gy is <3%. Patients with PSA values 10–19.9 ngm/ml and 20+ ngm/ ml benefit from dose escalation beyond 70 Gy. Treatment beyond 75 Gy results in >10% serious morbidity unless special precautions are taken to protect the rectal mucosa. All levels of severity of radiation morbidity show a dose response and combined with the dose response for bNED survival these data allow the optimization of treatment.

Relationship of tumor DNA-ploidy to serum prostate-specific antigen doubling time after radiotherapy for prostate cancer.

DNA-ploidy is a strong prognostic factor for prostate cancer patients treated with definitive external beam radiotherapy. Using DNA/nuclear protein flow cytometry, three prognostic groups based on DNA-ploidy were identified: from good to poor, these are diploid, near-diploid, and nondiploid tumors. Since recent evidence indicates that the rate at which prostate-specific antigen (PSA) increases in the presence of biochemical failure is predictive of the time to clinical relapse, we examined the relationship between DNA-ploidy and PSA doubling time (PSA-DT). Formalin-fixed paraffin-embedded tissues from 76 patients treated at M.D. Anderson Cancer Center with definitive radiotherapy alone were analyzed for ploidy using DNA/nuclear protein flow cytometry. Of these, 24 of the 27 patients with a rising PSA profile had three or more post-treatment PSA values from which the PSA-DTs were calculated. PSA-DTs were estimated using nonlinear regression techniques. The average PSA-DT for the 24 patients in this cohort was 11.3 +/- 10.5 months (+/- SD) with a median of 8.4 months. Diploidy (n = 3) was associated with a PSA-DT of 27.0 +/- 22.8 months, near-diploidy (n = 7) with a PSA-DT of 12.2 +/- 5.7 months, and non-diploidy (n = 14) with a PSA-DT of 7.5 +/- 5.7 months (p = 0.004, Spearman rank test). Stage, grade, and pretreatment PSA, as well as the endpoints of local control, freedom from metastases, and freedom from any relapse, did not correlate significantly with PSA-DT values. However, when patients were subdivided by PSA-DT into those with values 10 months or less (n = 14) and those more than 10 months (n = 10), there was a correlation with 3-year actuarial freedom from relapse: 28% and 74%, respectively (p < 0.01, log-rank). This subdivision of PSA-DT also correlated with DNA-ploidy (p = 0.03, chi-square) and stage (p = 0.04). The results show that there is a significant correlation of DNA-ploidy with PSA-DT. Diploidy was associated with the longest PSA-DTs, near-diploidy with intermediate PSA-DTs, and nondiploidy with short PSA-DTs. Patients with short PSA-DTs also had significantly higher actuarial rates of disease relapse at 3 years. These data confirm that PSA-DT is a strong predictor of tumor behavior and that patients who have nondiploid tumors probably require more aggressive, combined modality, treatment.

Serum prostate-specific antigen after radiation therapy for clinically localized prostate cancer: Prognostic implications

Purpose : Serum prostate-specific antigen (PSA) levels following definitive radiation for prostate cancer are increasingly recognized as the most sensitive means to monitor disease status. However, beyond general agreement that patients fare poorly when posttreatment PSA levels fail to normalize, many questions relative to postirradiation PSA remain unanswered. This study evaluates the potential prognostic value of postirradiation PSA in a large cohort of patients followed with serial PSA determinations. Methods and Materials : We analyzed disease outcome in 427 patients with clinical stages T 1 (122 men), T 2 (147 men), T 3 (152 men), and T 4 (six men) prostate cancer receiving definitive external radiation as sole therapy and followed for times ranging from 9–73 months (median 30 months) with a total of 2260 posttreatment PSA values. Results : Excluding three patients who died due to intercurrent illness without a posttreatment PSA, postirradiation PSA fell in 416 of 424 men (98%). Prostate-specific antigen levels continued to fall for up to 12 months but there was no evidence of significant declines beyond that. The time to nadir PSA was: 3 months, 60 patients; 6 months, 68 patients, 9 months 148 patients; 12 months, 144 patients. Time to nadir was not a significant determinant of outcome. Prostate-specific antigen levels at 3 and 6 months and the nadir level were individually highly correlated with outcome. In multivariate analyses of posttreatment values, only the nadir value was independently significant, with increasing relapse rates as its value was higher. It retained significance when pretreatment PSA level was included in the model. Nadir values ranged from undetectable (52 patients) to 20.3 ng/ml with a median of 1.1 ng/ml. Nadir values down to 1 ng/ml were prognostic; below 1 ng/ml (182 patients) the nadir value no longer yielded prognostic information additional to that inherent in the pretreatment value. Only patients with nadir levels < 1 ng/ml fared well (5-year incidence of relapse or rising PSA 17%); however, if the pretreatment level exceeded 30 ng/ml, then even a nadir level < 1 ng/ml was associated with a 40% failure rate at 5 years. Conclusion : The nadir PSA value after radiation is a significant posttreatment determinant of outcome and was second only to the pretreatment value. Surprisingly low nadir values were prognostically significant. Only patients whose nadir falls below 1 ng/ml can be said to have achieved a biochemical complete remission. However, even such low nadir values do not portend durable disease control for patients with high pretreatment PSA levels.

Prostate Specific Antigen after External Beam Radiotherapy for Prostatic Cancer: Followup

Between 1986 and 1989, 117 patients with pretreatment and serial posttreatment prostate specific antigen values received external beam radiotherapy at our hospital. Followup ranged from 0.6 to 5.9 years (mean 2.7). No patient had hormonal manipulation before distant recurrence. Biochemical relapse, defined as an increasing prostate specific antigen level after treatment, was observed in 44 patients. To date 30 of these 44 patients (68%) have had clinical relapse. The prognostic factors of advanced local stage, high Gleason score and high elevations of pretreatment prostate specific antigen values predicted for biochemical relapse and subsequent clinical failure. The interval between biochemical and clinical relapse was 156 ± 46 days. Biochemical relapse is an important end point that can be used to determine the effect of treatment in prostatic cancer research.

Prostate-specific antigen as a prognostic factor for prostate cancer treated by external beam radiotherapy

The potential prognostic significance of prostate-specific antigen (PSA) serum concentrations was evaluated in 171 patients with stages A2 to C adenocarcinoma of the prostate treated with external beam radiotherapy. After a median follow-up of 17 months, 12 patients sustained relapse of disease and PSA levels were found to be prognostically significant in three ways. (a) Pretreatment PSA level: none of 59 patients with a pretreatment PSA level ≤ 4 ng/ml relapsed to date and only one developed a subsequently rising PSA profile; 7 of 102 patients (7%) with a pretreatment PSA level in the range 4–40 ng/ml relapsed and 17 (17%) showed a rising PSA profile; 5 of 10 patients (50%) with a pretreatment PSA level ≥ 40 ng/ml relapsed and six (60%) developed rising PSA values. The differences were significant and were maintained when patients were stratified by stage or grade. (b) PSA level at 6 months: for patients with pretreatment PSA levels in the range 4–40 ng/ml, a 6-month value >2 ng/ml predicted a significantly worse outcome than a 6-month value < 2 ng/ml. (c) Rising post-treatment PSA values: following a radiation-related nadir in PSA levels, 24 patients experienced rising PSA values and 8 (33%) relapsed at a median time of 5 months after onset of the rising values—a significantly higher relapse rate than observed in patients with non-rising PSA values. Whether the majority, or all, of the patients with rising PSA levels relapse, requires further follow-up. In conclusion, serum PSA levels are strong prognostic determinants of outcome following radiotherapy for prostate cancer and appear to add prognostic information independently of tumor stage and grade.