Post-treatment Prostate-specific Antigen Nadir Research Articles

Proton Therapy for Localized Prostate Cancer: Long-Term Clinical Outcomes at a Comprehensive Cancer Center

<h3>Purpose/Objective(s)</h3> To assess the effectiveness and toxicity of proton therapy for patients with localized prostate cancer at a comprehensive cancer center. <h3>Materials/Methods</h3> Patients (n=2773) participating in two prospective clinical trials were treated from May 2006 through January 2020 at a comprehensive care center and stratified according to the National Comprehensive Cancer Network guidelines (n=640 low-risk [LR], n=850 favorable-intermediate risk [F-IR], n=851 unfavorable-intermediate risk [U-IR], n=315 high risk [HR], and n=117 very high risk [VHR]). Median patient age was 66 years; median follow-up time was 7.0 years. Median prostate-specific antigen (PSA) level at 7 years was 0.3 ng/mL (interquartile range [IQR] 0.2–0.4). Pelvic lymph node irradiation was given to 29 of 2773 patients (1%) (2/851 [0.2%] U-IR, 11/315 [3.5%] HR, and 16/117 [13.7%] VHR). The median PT dose was 78 Gy in 1.8–2.0 Gy(RBE) per fraction; 63% of patients received 78 Gy(RBE) in 39 fractions, and 29% received 76 Gy(RBE) in 38 fractions. Androgen deprivation therapy (ADT) was used in 1471 patients (53%) (68/640 [10.6%] LR, 329/850 [38.7%] F-IR, 642/851 [75.4%] U-IR, 315/315 [100%] HR, and 117/117 [100%] VHR), with a median duration of 6 months for U-IR and 24 months for HR and VHR groups. Biochemical failure was defined as post-treatment nadir PSA level + 2 ng/mL. Toxicity was graded according to the modified RTOG/EORTC morbidity scale. Descriptive statistics and Kaplan-Meier estimates were used to assess toxicity and survival. <h3>Results</h3> Freedom from biochemical relapse (FFBR) rates at 5 and 10 years were 98.3% (95% confidence interval [CI] 96.9-99.1%) and 97% (95% CI 94.8-98.3%) for the LR group; 98.3% (95% CI 97.0-99.0%) and 93.6% (95% CI 90.6-95.7%) for the F-IR; 94.2% (95% CI 92.1-95.7%) and 90.2% (95% CI 87.3-92.5%) for the U-IR; 94.3% (95% CI 90.1-96.8%) and 85.2% (95% CI 77.1-90.8%) for the HR; and 86.1% (95% CI, 74.7-92.9%) and 68.5% (95% CI, 50.9-82.1%) for the VHR group. Two patients died of prostate cancer, one VHR (at 19.5 months) and the other U-IR (at 28.5 months). The overall rate of acute grade ≥3 genitourinary (GU) toxicity was 6/2773 (0.22%). The overall rates of late grade ≥3 GU and gastrointestinal (GI) toxicities were 23/2773 (0.83%) and 26/2773 (0.94%). Maximum toxicities experienced were grade 4 acute GU in 1 patient, grade 4 late GU in 2 patients, and grade 4 late GI in 6 patients. <h3>Conclusion</h3> Long-term clinical outcomes for men treated with proton therapy for localized prostate cancer were excellent in all risk groups. The benefits of pelvic lymph node radiation therapy may be greatest in the VHR group, whereas the benefits of ADT may be highest in the U-IR, HR, and VHR groups.

Report of a Large Cohort of Intermediate-Risk Prostate Cancer Patients Treated with Cs-131 Brachytherapy

The intermediate-risk (IR) group of prostate cancer patients is extremely heterogenous. Patients are sub-classified into favorable-IR (FIR) and unfavorable-IR (UIR) groups due to variable prognoses, leading to significant treatment variations. We sought to evaluate our institutional outcomes utilizing Cs-131 prostate brachytherapy (PB) for IR patients and elucidate which factors are important for driving more aggressive treatment. We reviewed a prospectively collected database of men treated with Cs-131 PB between 2006-2019. Patients with less than 24-months follow-up were excluded. Patients were classified as IR if they had one of the following factors: Gleason Score 7, prostate specific antigen (PSA) >10 but < 20 ng/mL, or T2b-c on clinical exam. We defined UIR patients as having either Grade Group (GG) 3 or >1 IR factors. Our general treatment schema was to treat FIR with PB alone (115 Gy) and UIR with combined external beam radiation therapy (EBRT) to 45 Gy + PB boost (85 Gy), though this was somewhat variable. The Kaplan-Meier method was used to estimate actuarial event-time probabilities for biochemical failure (BF). BF was defined as a serum PSA at least 2 ng/mL greater than posttreatment nadir PSA. Cox regression analysis was performed to identify predictors for BF. These factors included: GG, UIR subgroup, treatment (PB alone vs combined modality), ADT use, age (≤67 vs >67), clinical T-stage, PSA (<10 vs ≥10-20), and >1 IR factors. A total of 327 patients with a median follow-up of 70.6 months (IQR 45.9-102.7 months) were identified. Median age was 67 (IQR 62-72). ADT was used in 12.5% of patients. Most patients (57.5%) were classified as FIR. Of the 139 patients in the UIR subgroup, 69.1% met UIR criteria by virtue of GG 3 only and 30.9% by having >1 IR factor. Twenty-eight patients (20.1%) had a GG 3 and >1 IR factor. FIR patients had a 5-year BF rate (BFR) of 2.5% (SE 0.012). The 5-year BFRs for FIR patients treated with PB alone (81.4%) and combined modality (18.6%) were 1.7% (SE 0.012) and 5.0% (SE 0.035), respectively (p = 0.18). UIR patients had a 5-year BFR of 10.9% (SE 0.030) and were most commonly treated with EBRT+PB (61.9%). Five-year BFRs were 14.0% (SE 0.078) and 10.1% (SE 0.032) for UIR patients treated with PB alone and combined modality, respectively (p = 0.91). UIR patients by virtue of GG 3 only (n = 68) had a 5-year BFR of 13.0% (SE 0.047). The 5-year BFR for UIR due to >1 IR factors (n = 71) was 8.9% (SE 0.038). Six patients had 3 IR factors with a 5-year BFR of 50% (SE 0.25). On multivariate analysis, UIR subgroup was the only significant predictor for BF (p = 0.02; HR 2.49, 95% CI 1.15-5.41). The FIR subgroup is a distinct entity from the UIR subgroup with excellent outcomes when treated with Cs-131 PB alone. UIR patients have excellent outcomes with combined EBRT + PB. The majority of UIR patients do not require ADT, though the group that would benefit still needs to be defined.

Primary Cryotherapy for High-Grade Clinically Localized Prostate Cancer: Oncologic and Functional Outcomes from the COLD Registry.

To evaluate the oncological and functional outcomes of primary cryotherapy in men with clinically localized, high-grade prostate cancer. We included all men with biopsy Gleason score ≥8, localized (cT1-2) disease with a serum prostate-specific antigen (PSA) ≤50 ng/mL from the Cryo On-Line Data (COLD) registry. The primary outcome was biochemical progression free survival (BPFS) as defined by the Phoenix criteria (nadir PSA +2 ng/mL). Secondary outcomes of continence (defined as strictly no leak) and potency (able to have intercourse) were patient reported. Factors influencing BPFS were evaluated individually using Kaplan Meier and in a multivariate model using Cox regression. Altogether, 300 men were included for analysis. The median follow-up was 18.2 months (mean 28.4) and median BPFS was 69.8 months. Based on Kaplan-Meier analysis, the estimated 2- and 5-year BPFS rate was 77.2% and 59.1%, respectively. Neoadjuvant hormonal therapy was administered to 41% of men and this tended to occur in men with larger prostates, likely as a technical consideration for downsizing before cryosurgery. At multivariate analysis, the presence of Gleason score 9 or 10 (Hazard Ratio [HR] 1.9) and a posttreatment PSA nadir of ≥0.4 ng/mL (HR 5.7) were the only significant variables associated with biochemical progression using Cox regression. Complete continence was noted in 90.5% of men and potency in 17% of men at the 12-month follow-up. The incidence of rectourethral fistulae and urinary retention requiring intervention beyond temporary catheterization was 1.3% and 3.3%, respectively. Primary cryotherapy appears to be effective and safe in the community setting for high-grade, clinically localized prostate cancer in the short term.

Three linked nomograms for predicting biochemical failure in prostate cancer treated with radiotherapy plus androgen deprivation therapy.

Nomograms were established to predict biochemical recurrence (BCR) after radiotherapy (RT) with a low weight of the characteristic variables of RT and androgen deprivation therapy (ADT). Our aim is to provide a new stratified tool for predicting BCR at 4 and 7 years in patients treated using RT with radical intent. A retrospective, nonrandomized analysis was performed on 5044 prostate cancer (PCa) patients with median age 70 years, who received RT-with or without ADT-between November 1992 and May 2007. Median follow-up was 5.5 years. BCR was defined as a rise in serum prostate-specific antigen (PSA) of 2 ng/ml over the post-treatment PSA nadir. Univariate association between predictor variables and BCR was assessed by the log-rank test, and three linked nomograms were created for multivariate prognosis of BCR-free survival. Each nomogram corresponds to a category of the Gleason score-either 6,7, or 8-10-and all of them were created from a single proportional hazards regression model stratified also by months of ADT (0, 1-6, 7-12, 13-24, 25-36, 36-60). The performance of this model was analyzed by calibration, discrimination, and clinical utility. Initial PSA, clinical stage, and RT dose were significant variables (p < 0.01). The model showed a good calibration. The concordance probability was 0.779, improving those obtained with other nomograms (0.587, 0.571, 0.554) in the database. Survival curves showed best clinical utility in a comparison with National Comprehensive Cancer Network (NCCN) risk groups. For each Gleason score category, the nomogram provides information on the benefit of adding ADT to a specific RT dose.

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

Correlation of pretreatment clinical parameters and PSA nadir after high-intensity focused ultrasound (HIFU) for localised prostate cancer

To determine which pretreatment clinical parameters were predictive of a low prostate-specific antigen (PSA) nadir following high-intensity focused ultrasound (HIFU) treatment. Retrospective study of patients with clinically localised prostate cancer undergoing HIFU at a single centre between December 1997 and September 2009. Whole-gland treatment was applied. Patients also included if they had previously undergone transurethral resection of the prostate (TURP). TURP was also conducted simultaneously to HIFU. Biochemical failure based on Phoenix definition (PSA nadir + 2). Univariate and multivariate analysis of pretreatment clinical parameters conducted to assess those factors predictive of a PSA nadir ≤0.2 and >0.2 ng/ml. Mean (SD) follow-up was 6.2 (2.8) years; median (range) was 6.3 (1.1-12.2) years. Kaplan-Meier estimate of biochemical disease-free survival rate at 8 years was 83 and 48 % for patients achieving a PSA nadir of ≤0.2 and >0.2 ng/ml, respectively. Prostate volume and incidental finding of cancer were significant predictors of low PSA nadir (≤0.2 ng/ml). Prostate volume and incidental finding of cancer could be predictors for oncologic success of HIFU based on post-treatment PSA nadir.

Prostate-Specific Antigen Kinetics under Androgen Deprivation Therapy and Prostate Cancer Prognosis

Objectives: To compare the difference in characteristics of post-treatment prostate-specific antigen (PSA) kinetics among respective patients and their influence on disease prognosis. Methods: A cohort of totally 332 eligible patients with histologically confirmed and hormonally naïve prostate cancer, identified from the patients' database of Huashan Hospital, all received combined androgen deprivation therapy including bilateral orchiectomy or luteinizing hormone-releasing hormone antagonists with the oral administration of flutamide 250 mg t.i.d. All patients had their serum PSA level tested at least every 3 months in the first 2 years and at least once a half year from the third year on. PSA nadir, time to PSA nadir (TTPN), PSA normalization (<4 ng/ml), undetectable PSA level (<0.2 ng/ml), biochemical failure, overall survival and cancer-specific survival were analyzed. Results: PSA normalization, TTPN, and reaching the undetectable PSA level perhaps were the independent risk factors for predicting the three types of prognosis. Probably the best cut-off of PSA nadir was 0.2 ng/ml (sensitivity 65.7%, specificity 80.6%) and the best cut-off of TTPN was 10 months (sensitivity 71.6%, specificity 63.9%). Conclusions: These results implied that a lower level of PSA nadir and longer TTPN can predict a better disease prognosis.

Posttreatment Prostate Specific Antigen Nadir Predicts Prostate Cancer Specific and All Cause Mortality

We investigated whether the prostate specific antigen nadir predicts prostate cancer specific and all cause mortality in men treated in a randomized trial of radiation with or without 6 months of androgen deprivation therapy. The study included 204 men with cT1b-T2bN0M0 prostate adenocarcinoma and at least 1 unfavorable factor, including prostate specific antigen less than 10 to 40 ng/ml, Gleason 7 or greater, or T3 on magnetic resonance imaging. We performed Fine and Gray regression, and Cox multivariable analysis to determine whether an increasing prostate specific antigen nadir was associated with prostate cancer specific and all cause mortality, adjusting for treatment, age, Adult Comorbidity Evaluation 27 score and cancer prognostic factors. At a 6.9-year median followup median prostate specific antigen nadir was 0.7 ng/ml for radiation alone and 0.1 ng/ml for radiation plus androgen deprivation therapy. The prostate specific antigen nadir (adjusted HR 1.18/ng/ml increase, 95% CI 1.07-1.31, p=0.001) and Gleason 8 or greater (adjusted HR 8.05, 95% CI 1.01-64.05, p=0.049) significantly predicted increased prostate cancer specific mortality. Moderate/severe comorbidity carried a decreased risk (adjusted HR 0.13, 95% CI 0.02-0.96, p=0.045). Higher prostate specific antigen nadir (adjusted HR 1.10/ng/ml increase, 95% CI 1.04-1.17), older age (adjusted HR 1.10/year, 95% CI 1.04-1.15) and interaction between comorbidity score and randomization arm (each p<0.001) increased the all cause mortality risk. Men who achieved a prostate specific antigen nadir of the median value or less had lower estimated prostate cancer specific and all cause mortality at 7 years (3.7% vs 18.3%, p=0.0005 and 31.5% vs 55.0%, p=0.002). Posttreatment prostate specific antigen nadir is significantly associated with the risk of prostate cancer specific and all cause mortality after radiation with or without androgen deprivation therapy. A suboptimal prostate specific antigen nadir may identify candidates for earlier intervention to prolong survival.

Posttreatment Prostate Specific Antigen Nadir Predicts Prostate Cancer Specific and All Cause Mortality

Posttreatment Prostate Specific Antigen Nadir Predicts Prostate Cancer Specific and All Cause Mortality

Post-Treatment Prostate-Specific Antigen Nadir is Predictive of All-Cause Mortality: A Reanalysis of the Dana Farber Cancer Institute Radiation With or Without Androgen Deprivation Therapy Randomized Trial

Post-Treatment Prostate-Specific Antigen Nadir is Predictive of All-Cause Mortality: A Reanalysis of the Dana Farber Cancer Institute Radiation With or Without Androgen Deprivation Therapy Randomized Trial

Interval to Biochemical Failure Highly Prognostic for Distant Metastasis and Prostate Cancer-Specific Mortality After Radiotherapy

Few biochemical parameters have been related to mortality. The present study examined the clinical utility of the interval to biochemical failure (IBF) as a prognostic factor for distant metastasis (DM) and prostate cancer-specific mortality (PCSM) after radiotherapy. The study group consisted of 211 T1c-T3Nx-N0M0 patients who had experienced BF among 1,174 men treated with three-dimensional conformal radiotherapy alone. Biochemical failure was defined as a post-treatment prostate-specific antigen (PSA) level of at, or greater than, the PSA nadir plus 2 ng/mL. Cox proportional hazards modeling was used to identify independent predictors of DM and PCSM on multivariate analysis. An IBF of <18 months was independently predictive for DM (p = 0.008), as was a Gleason score of 7-10 (p = 0.0005), PSA nadir >or=2 ng/mL (p = 0.04), and decreasing radiation dose (p = 0.02) on multivariate analysis, including increasing pretreatment PSA level, PSA nadir >or=2.5 ng/mL, PSA doubling time of <3 months, and Stage T3 disease. An IBF of <18 months was the only predictor of PCSM (p = 0.0003) in the same model. The actuarial 5-year DM rate for an IBF of <18 vs. >or=18 months was 52% vs. 20% (p < 0.0001), and the actuarial PCSM rate was 36% vs. 6%, respectively (p = 0.0001). The IBF is an important descriptor of the PSA kinetics after radiotherapy to identify men at high risk of clinical failure and death. A IBF of <18 months could aid in selecting men for early, aggressive salvage therapy or participation in a clinical trial.

Transperineal Permanent Seed Implantation of “Low-Risk” Prostate Cancer

To evaluate 5-year prostate-specific antigen (PSA) relapse-free survival of transperineal permanent seed implantation (TPSI) in 118 patients with “low-risk” prostate cancer, that means stage cT1c–T2a, Gleason Score < 7, and initial PSA value < 10 ng/ml. From 04/1999 to 06/2002, a total of 118 patients underwent a mono-TPSI, using ultrasound-based preplanning and intraoperative verification by both ultrasound and conventional fluoroscopy as well as postoperative CT planning. Patients were monitored during the 1st year in 3-month intervals, and in 6-monthly intervals from then onward. Biochemical failure was defined according to ASTRO criteria with three consecutive PSA rises observed from a posttreatment nadir PSA value. The median follow-up was 48.9 months (range: 37.0–80.2 months). 114 patients were eligible, four patients were lost to follow-up. For the entire group, PSA relapse-free survival at 5 years was 94.7%, with six patients (5.3%) having a PSA relapse between 8 and 20 months after implantation. In the bNED patients (no biochemical evidence of disease), PSA values were < 0.2 ng/ml in 82.5% (94/114 patients), < 0.5 ng/ml in 13.2% (15/114 patients), < 1.0 ng/ml in 2.6% (3/114 patients), and < 1.5 ng/ml in 1.7% (2/114 patients). In summary, PSA values < 0.2 ng/ml, < 0.5 ng/ml and < 1.0 ng/ml occurred in 82.5%, 95.7% and 98.3%, respectively. Out of the six patients with recurrent disease, three had a local tumor recurrence only, and three developed distant metastases. In low-risk prostate cancer patients, TPSI with intraoperative ultrasound-based treatment planning and fluoroscopy leads to excellent local tumor control and PSA relapse-free survival.

Clinical Features and Treatment Outcome of Hispanic Men With Prostate Cancer Following External Beam Radiotherapy

We retrospectively analyzed the clinical characteristics and outcomes of Hispanic men compared with other groups who underwent radiotherapy alone for localized or locally advanced prostate cancer. Between April 1987 and January 1998, 964 men who underwent full dose external beam radiotherapy alone for localized or locally advanced prostate cancer were included in the study. Patient medical records were reviewed for pertinent information. Of the 964 men 810 were non-Hispanic white, 54 were Hispanic and 86 were black Americans. The most significant difference among the groups was in the proportion of patients who presented with initial prostate specific antigen (PSA) greater than 20 ng/ml (22% of Hispanic vs 11% of white men, p = 0.0012). In addition, 17% of Hispanic men had a Gleason score of 8 or greater compared with 11% of white men (p = 0.0265). A greater proportion of Hispanic patients also had a less favorable posttreatment PSA nadir of greater than 1 ng/ml compared with white patients, (44% vs 26%, p = 0.0214), which may have translated into a trend toward a lower 5-year disease-free survival rate in Hispanics vs white men (52% vs 65%, p = 0.07). Hispanic men presented with higher PSA and higher grade prostate cancer than white men. Furthermore, a higher percent of Hispanic men had a PSA nadir of 1 ng/ml or greater after radiotherapy, which may have been responsible for their trend toward a decreased 5-year disease-free survival rate compared with white men. Improved screening and early detection may improve disease-free survival in Hispanic men with localized prostate cancer.

Modifying the American Society for Therapeutic Radiology and Oncology Definition of Biochemical Failure to Minimize the Influence of Backdating in Patients With Prostate Cancer Treated With 3-dimensional Conformal Radiation Therapy Alone

Adoption of the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definition has been critical for evaluating and comparing outcome following treatment with radiation. However, since its almost universal adoption, several points have remained controversial, notably backdating the date of failure to the point midway between the posttreatment prostate specific antigen (PSA) nadir and the first increase. We evaluated the impact of backdating on no biochemical evidence of disease (bNED) control and suggest changes in the definition. Between April 1, 1989 and November 30, 1998, 1,017 patients with nonmetastatic prostate cancer were treated with 3-dimensional conformal radiation therapy alone. bNED control was defined using the ASTRO consensus definition. bNED failure was calculated from the time midway between the posttreatment PSA nadir and the first of the 3 consecutive increases in PSA (date of failure A). Four alternate failure time points were chosen, including backdating to the date of the first increase in PSA after the nadir, the date between the first and second consecutive PSA increases, the date between the second and third consecutive PSA increases, and the date of the third increase in PSA after the nadir (dates of failure 1 to 4). Kaplan-Meier estimates were calculated for all definitions of failure as well as hazard functions with time. Subset analyses based on prognostic group and followup time were also performed. The 10-year Kaplan-Meier bNED control rates were 64%, 52%, 47%, 42% and 39% using dates of failure A and 1 to 4, respectively. These differences persisted when patients were stratified by prognostic group. These same differences in bNED control were observed for the long-term followup subset, in which 10-year bNED control rates were 48%, 47%, 44%, 41% and 39% using dates of failure A and 1 to 4, respectively. Adoption of the ASTRO consensus definition has been crucial for evaluating outcome in the radiation oncology community. However, the date of failure should be moved from the current point to one closer to the point at which failure is declared. Additional analysis with large numbers of patients from multiple institutions is necessary to determine the point.

Hazard Rates of Disease Progression After External Beam Radiotherapy for Clinically Localized Carcinoma of the Prostate

We established hazard rates for disease progression at different intervals after external beam radiotherapy alone in patients with clinically localized prostate cancer. We determined the likelihood of biochemical failure in those free of disease 5 years after radiotherapy and identified those at risk for early versus late biochemical failure. We reviewed the records of 964 patients treated with full dose external beam radiotherapy alone for T1 to T4, NxM0 prostate cancer. Followup prostate specific antigen (PSA) was measured 3 months after the completion of radiotherapy and every 3 to 6 months thereafter. Yearly hazard rates for biochemical failure were calculated each followup year. Median followup of the whole study group was 48 months. Overall 5 and 10-year biochemical disease-free survival rates were 63.7% and 53.6%, respectively. Patients had a peak overall hazard rate 2 years after treatment. The hazard rate then decreased until year 6, when it increased slightly and remained elevated even at year 10. This late increase in the overall hazard rate was associated with late increases in the hazard rate in men with favorable prognostic factors, namely pretreatment PSA less than 10 ng./ml., Gleason score less than 5, clinical T stage T1 or T2, posttreatment PSA nadir less than 0.99 ng./ml. or radiation dose less than 68 Gy. In 13 of the 307 patients (3.9%) with biochemical failure the failure occurred more than 5 years after initial treatment. The peak risk of biochemical failure is 2 years after radiotherapy. Patients are at slight but persistent risk for biochemical failure more than 5 years after treatment. Hazard rate calculations beyond the median followup of 4 years can underestimate the true hazard.

Posttreatment prostate-specific antigen nadir highly predictive of distant failure and death from prostate cancer

Purpose: To link posttreatment biochemical profiles to distant failure and cause-specific survival by assessing the relationship between posttreatment prostate-specific antigen (PSA) nadir and PSA doubling time (PSADT) with these outcome measures.Methods and Materials: A total of 615 men were treated at the Fox Chase Cancer Center between April 1989 and December 1995 with three-dimensional conformal radiotherapy alone (median dose 73 Gy). The median follow-up was 64 months (range 2–135). Kaplan-Meier methods were used to estimate the rates of biochemical control, freedom from distant metastasis (FDM), and cause-specific survival. Multivariate predictors of outcome were assessed using stepwise Cox regression analysis.Results: Multivariate analyses demonstrated that the predictors of improved biochemical control were a lower PSA nadir (p <0.0001), lower pretreatment PSA level (p <0.0001), Gleason score of 2–6 (p = 0.001), Stage T1-T2a tumors (p = 0.03), and higher RT dose (p = 0.02). The predictors of improved FDM were a lower PSA nadir (p <0.0001), longer interval to nadir from start of treatment (p = 0.0002), Gleason score of 2–6 (p = 0.005), androgen deprivation for biochemical failure (p = 0.001), and Stage T1-T2a tumors (p = 0.01). The predictors of improved cause-specific survival were a lower PSA nadir (p = 0.006) and longer interval to nadir from the start of treatment (p = 0.03). The 8-year FDM rate was 96%, 89%, and 61% for PSA nadir values of ≤1.0, 1.1–2.0, and >2.0 ng/mL (p <0.0001), respectively. The 8-year cause-specific survival rate was 97%, 96%, and 78% for posttreatment PSA nadir values of ≤1.0, 1.1–2.0, and >2.0 ng/mL (p <0.0001), respectively. For patients with sufficient PSA follow-up for PSADT calculations (n = 136), multivariate analysis of FDM from the time of biochemical failure demonstrated that androgen deprivation (p = 0.001), longer PSADT (p = 0.003), lower PSA nadir (p = 0.02), and longer interval to nadir from start of treatment (p = 0.04) were independent predictors of improved FDM.Conclusion: This is the first study, to our knowledge, to demonstrate the overwhelming predictive power of posttreatment PSA nadir for distant failure and death from prostate cancer. It is also the first study, to our knowledge, to demonstrate a strong association between posttreatment PSADT and distant failure. The results provide new information regarding disease progression as a function of posttreatment PSA profiles (time to achieve nadir from start of treatment, nadir, and PSADT) and the timing of androgen deprivation for biochemical relapse. This study may be used for the early identification of patients at high risk of distant metastasis and who may be directed to applicable systemic treatment clinical trials.

Relationship between prostate volume, prostate-specific antigen nadir, and biochemical control

Purpose: In patients treated with definitive three-dimensional conformal radiotherapy (3D-CRT) for localized prostatic adenocarcinoma, we sought to evaluate the relationship between pretreatment prostate gland volume and posttreatment prostate-specific antigen (PSA) nadir, as well as the relationship of prostate volume and PSA nadir with biochemical control (bNED). Two subgroups were studied: favorable (PSA <10 ng/mL, Gleason score 2–6, and T1-T2A) and unfavorable (one or more: PSA ≥10 ng/mL, Gleason score 7–10, T2B-T3).Methods and Materials: A total of 655 men (n = 271 favorable and 384 unfavorable) were treated with 3D-CRT alone between May 1989 and November 1997. All patients had information on prostate volume and a minimum follow-up of 24 months (median 56, range 24–126). Of the 655 men, 481 (n = 230 favorable and 251 unfavorable) remained bNED at time of analysis, with biochemical failure defined in accordance with the American Society for Therapeutic Radiology and Oncology consensus definition. Factors analyzed for predictors of bNED included pretreatment prostate volume, posttreatment PSA nadir, pretreatment PSA, palpation T stage, Gleason score, center of the prostate dose, and perineural invasion (PNI). We also analyzed pretreatment prostate volume and its correlation to prognostic factors. For bNED patients, the relationship between PSA nadir and prostate volume was evaluated.Results: On multivariate analysis, prostate volume (p = 0.04) and palpation T stage (p = 0.02) were the only predictors of biochemical failure in the favorable group. On multivariate analysis of the unfavorable group, pretreatment PSA (p <0.0001), Gleason score (p = 0.02), palpation T stage (p = 0.009), and radiation dose (p <0.0001) correlated with biochemical failure, and prostate volume and PNI did not. For all 481 bNED patients, a positive correlation between pretreatment volume and PSA nadir was demonstrated (p <0.0001). Subgroup analysis of the favorable and unfavorable patients also demonstrated a positive correlation between prostate volume and PSA nadir (p = 0.003 and p = 0.0002, respectively). Using multiple regression analysis, the following were found to be predictive of PSA nadir in all bNED patients: prostate volume (p <0.0001), pretreatment PSA (p <0.0001), palpation T stage (p = 0.0002), and radiation dose (p = 0.0034). Gleason score and PNI were not predictive. For the favorable group, palpation T stage (p = 0.0006), pretreatment PSA (p = 0.0083), prostate volume (p = 0.0186), and Gleason score (p = 0.0592) were predictive of PSA nadir, and PNI and radiation dose were not predictive. In the unfavorable group, prostate volume (p = 0.0024), radiation dose (p = 0.0039), pretreatment PSA (p = 0.0182), and palpation T stage (p = 0.0296) were predictive of PSA nadir, and Gleason score and PNI were not predictive.Conclusion: This report is the first demonstration that prostate volume is predictive of PSA nadir for patients who are bNED in both favorable and unfavorable subgroups. PSA nadir did not correlate with bNED status in the favorable patients, but it was strongly predictive in the unfavorable patients. Prostate gland volume was also predictive of bNED failure in the favorable but not the unfavorable group.

A survival model for fractionated radiotherapy with an application to prostate cancer

This paper explores the applicability of a mechanistic survival model, based on the distribution of clonogens surviving a course of fractionated radiation therapy, to clinical data on patients with prostate cancer. The study was carried out using data on 1100 patients with clinically localized prostate cancer who were treated with three-dimensional conformal radiation therapy. The patients were stratified by radiation dose (group 1: <67.5 Gy; group 2: 67.5–72.5 Gy; group 3: 72.5–77.5 Gy; group 4: 77.5–87.5 Gy) and prognosis category (favourable, intermediate and unfavourable as defined by pre-treatment PSA and Gleason score). A relapse was recorded when tumour recurrence was diagnosed or when three successive prostate specific antigen (PSA) elevations were observed from a post-treatment nadir PSA level. PSA relapse-free survival was used as the primary end point. The model, which is based on an iterated Yule process, is specified in terms of three parameters: the mean number of tumour clonogens that survive the treatment, the mean of the progression time of post-treatment tumour development and its standard deviation. The model parameters were estimated by the maximum likelihood method. The fact that the proposed model provides an excellent description both of the survivor function and of the hazard rate is prima facie evidence of the validity of the model because closeness of the two survivor functions (empirical and model-based) does not generally imply closeness of the corresponding hazard rates. The estimated cure probabilities for the favourable group are 0.80, 0.74 and 0.87 (for dose groups 1–3, respectively); for the intermediate group: 0.25, 0.51, 0.58 and 0.78 (for dose groups 1–4, respectively) and for the unfavourable group: 0.0, 0.27, 0.33 and 0.64 (for dose groups 1–4, respectively). The distribution of progression time to tumour relapse was found to be independent of prognosis group but dependent on dose. As the dose increases the mean progression time decreases (41, 28.5, 26.2 and 14.7 months for dose groups 1–4, respectively). This analysis confirms that, in terms of cure rate, dose escalation has a significant positive effect only in the intermediate and unfavourable groups. It was found that progression time is inversely proportional to dose, which means that patients recurring in higher dose groups have shorter recurrence times, yet these groups have better survival, particularly long-term. The explanation for this seemingly illogical observation lies in the fact that less aggressive tumours, potentially recurring after a long period of time, are cured by higher doses and do not contribute to the recurrence pattern. As a result, patients in higher dose groups are less likely to recur; however, if they do, they tend to recur earlier. The estimated hazard rates for prostate cancer pass through a clear-cut maximum, thus revealing a time period with especially high values of instantaneous cancer-specific risk; the estimates appear to be nonproportional across dose strata.

Prostate–Specific Antigen Levels and Clinical Response to Flutamide as the Second Hormone Therapy for Hormone–Refractory Prostate Carcinoma

Background: Some authors have recently reported that maximum androgen block (MAB), in which the nonsteroidal anti–androgen, flutamide, is used together with conventional hormone therapy such as castration or luteinizing hormone–releasing hormone analogue, is more effective for prostate cancer than conventional methods. However, others have reported that the effect of MAB on survival is minimal, and definite conclusions concerning MAB remain unclear. Conversely, using flutamide as a second–line hormone therapy after recurrence is also considered, but few authors have reported whether this therapeutic option is effective or for which patients it is effective.Materials and Methods: 124 patients with prostate cancer were diagnosed and followed at Kobe City General Hospital between 1995 and 1997. Twenty–two of these cases developed recurrence during first–line hormone therapy, and flutamide was prescribed in these cases. The prognostic value and effectiveness of flutamide were evaluated by measurement of serum prostate–specific antigen (PSA) at diagnosis, posttreatment nadir PSA level, PSA at the time of flutamide use, histological grade, recurrence–free time after firstline hormone therapy and age at the time of diagnosis.Results: Six of 9 cases whose post–treatment nadir PSA levels after initial hormone therapy were within the normal limit (<4 ng/ml) achieved complete remission (CR) with flutamide use, but no patient whose post–treatment nadir PSA level remained elevated achieved CR. PSA at diagnosis and PSA at the start of flutamide use were significantly lower for patients with CR. However, the results of multivariate logistic regression analysis demonstrated that only the post–treatment nadir PSA level was significantly correlated with prognosis of flutamide use.Conclusions: Flutamide use as second–line hormone therapy should be limited to cases in which first–line hormone therapy has been highly effective and for whom the post–treatment nadir PSA level was within normal limits, and other patients should undergo other therapies. By limiting flutamide use to patients in whom the effect of flutamide is considered to be maximal, the incidence of complications and medication costs can be decreased.

Conformal Proton Therapy for Prostate Carcinoma

Abstract Background: The role and optimum dose of radiation to eradicate prostate cancer continues to be evaluated. Protons offer an opportunity to increase the radiation dose to the prostate while minimizing treatment toxicity. Methods: Six hundred forty-three patients with localized prostate cancer were treated with protons, with or without photons. Treatments were planned with a 3D planning system; patients received 74–75 CGE (Cobalt Gray Equivalent) at 1.8–2.0 CGE per fraction. Patients were evaluated for response to therapy and treatment-related toxicity. Results: The overall clinical disease-free survival rate was 89% at 5 years. When post-treatment prostate-specific antigen (PSA) was used as an endpoint for disease control, the 4.5-year disease-free survival rate was 100% for patients with an initial PSA of 20.0, respectively. Patients in whom the post-treatment PSA nadir was below 0.5 ng/ml did significantly better than those whose nadir values were between 0.51–1.0 or > 1.0 ng/ml: the corresponding 5-year disease-free survival rates were 91%, 79%, and 40%, respectively. Minimal radiation proctitis was seen in 21% of patients; toxicity of greater severity was seen in less than 1%. Conclusion: Proton therapy to 74–75 CGE produced minimal treatment-related toxicity and excellent PSA normalization and disease-free survival in patients with low initial PSA levels. A prospective randomized dose-escalation trial is now underway to help define the optimum dose of radiation for patients with early stage prostate cancer.