Abstract Background Despite revisions in 2005 and 2014, the Gleason prostate cancer (PCa) grading system still has major deficiencies. Combining of Gleason scores into a three-tiered grouping (6, 7, ...8–10) is used most frequently for prognostic and therapeutic purposes. The lowest score, assigned 6, may be misunderstood as a cancer in the middle of the grading scale, and 3 + 4 = 7 and 4 + 3 = 7 are often considered the same prognostic group. Objective To verify that a new grading system accurately produces a smaller number of grades with the most significant prognostic differences, using multi-institutional and multimodal therapy data. Design, setting, and participants Between 2005 and 2014, 20 845 consecutive men were treated by radical prostatectomy at five academic institutions; 5501 men were treated with radiotherapy at two academic institutions. Outcome measurements and statistical analysis Outcome was based on biochemical recurrence (BCR). The log-rank test assessed univariable differences in BCR by Gleason score. Separate univariable and multivariable Cox proportional hazards used four possible categorizations of Gleason scores. Results and limitations In the surgery cohort, we found large differences in recurrence rates between both Gleason 3 + 4 versus 4 + 3 and Gleason 8 versus 9. The hazard ratios relative to Gleason score 6 were 1.9, 5.1, 8.0, and 11.7 for Gleason scores 3 + 4, 4 + 3, 8, and 9–10, respectively. These differences were attenuated in the radiotherapy cohort as a whole due to increased adjuvant or neoadjuvant hormones for patients with high-grade disease but were clearly seen in patients undergoing radiotherapy only. A five–grade group system had the highest prognostic discrimination for all cohorts on both univariable and multivariable analysis. The major limitation was the unavoidable use of prostate-specific antigen BCR as an end point as opposed to cancer-related death. Conclusions The new PCa grading system has these benefits: more accurate grade stratification than current systems, simplified grading system of five grades, and lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa. Patient summary We looked at outcomes for prostate cancer (PCa) treated with radical prostatectomy or radiation therapy and validated a new grading system with more accurate grade stratification than current systems, including a simplified grading system of five grades and a lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa.
To review the biochemical relapse-free survival (bRFS) rates after treatment with permanent seed implantation (PI), external beam radiotherapy (EBRT) <72 Gy (EBRT <72), EBRT ≥72 Gy (EBRT ≥72), ...combined seeds and EBRT (COMB), or radical prostatectomy (RP) for clinical Stage T1-T2 localized prostate cancer treated between 1990 and 1998.
The study population comprised 2991 consecutive patients treated at the Cleveland Clinic Foundation or Memorial Sloan Kettering at Mercy Medical Center. All cases had pretreatment prostate-specific antigen (iPSA) levels and biopsy Gleason scores (bGSs). Neoadjuvant androgen deprivation for ≤6 months was given in 622 cases (21%). No adjuvant therapy was given after local therapy. RP was used for 1034 patients (35%), EBRT <72 for 484 (16%), EBRT ≥72 for 301 (10%), PI for 950 (32%), and COMB for 222 patients (7%). The RP, EBRT <72, EBRT ≥72, and 154 PI patients were treated at Cleveland Clinic Foundation. The median radiation doses in EBRT <72 and EBRT ≥72 case was 68.4 and 78.0 Gy, respectively. The median follow-up time for all cases was 56 months (range 12–145). The median follow-up time for RP, EBRT <72, EBRT ≥72, PI, and COMB was 66, 75, 49, 47, and 46 months, respectively. Biochemical relapse was defined as PSA levels >0.2 for RP cases and three consecutive rising PSA levels (American Society for Therapeutic Radiology Oncology consensus definition) for all other cases. A multivariate analysis for factors affecting the bRFS rates was performed using the following variables: clinical T stage, iPSA, bGS, androgen deprivation, year of treatment, and treatment modality. The multivariate analysis was repeated excluding the EBRT <72 cases.
The 5-year bRFS rate for RP, EBRT <72, EBRT ≥72, PI, and COMB was 81%, 51%, 81%, 83%, and 77%, respectively (
p <0.001). The 7-year bRFS rate for RP, EBRT <72, EBRT ≥72, PI, and COMB was 76%, 48%, 81%, 75%, and 77%, respectively. Multivariate analysis, including all cases, showed iPSA (
p <0.001), bGS (
p <0.001), year of therapy (
p <0.001), and treatment modality (
p <0.001) to be independent predictors of relapse. Because EBRT <72 cases had distinctly worse outcomes, the analysis was repeated after excluding these cases to discern any differences among the other modalities. The multivariate analysis excluding the EBRT <72 cases revealed iPSA (
p <0.001), bGS (
p <0.001), and year of therapy (
p = 0.001) to be the only independent predictors of relapse. Treatment modality (
p = 0.95), clinical T stage (
p = 0.09), and androgen deprivation (
p = 0.56) were not independent predictors for failure.
The biochemical failure rates were similar among PI, high-dose (≥72 Gy) EBRT, COMB, and RP for localized prostate cancer. The outcomes were significantly worse for low-dose (<72 Gy) EBRT.
Abstract Background The natural history of prostate-specific antigen (PSA)-defined biochemical recurrence (BCR) of prostate cancer (PCa) after definitive local therapy is highly variable. Validated ...prediction models for PCa-specific mortality (PCSM) in this population are needed for treatment decision-making and clinical trial design. Objective To develop and validate a nomogram to predict the probability of PCSM from the time of BCR among men with rising PSA levels after radical prostatectomy. Design, setting, and participants Between 1987 and 2011, 2254 men treated by radical prostatectomy at one of five high-volume hospitals experienced BCR, defined as three successive PSA rises (final value >0.2 ng/ml), single PSA >0.4 ng/ml, or use of secondary therapy administered for detectable PSA >0.1 ng/ml. Clinical information and follow-up data were modeled using competing-risk regression analysis to predict PCSM from the time of BCR. Intervention Radical prostatectomy for localized prostate cancer and subsequent PCa BCR. Outcome measurements and statistical analysis PCSM. Results and limitations The 10-yr PCSM and mortality from competing causes was 19% (95% confidence interval CI 16–21%) and 17% (95% CI 14–19%), respectively. A nomogram predicting PCSM for all patients had an internally validated concordance index of 0.774. Inclusion of PSA doubling time (PSADT) in a nomogram based on standard parameters modestly improved predictive accuracy (concordance index 0.763 vs 0.754). Significant parameters in the models were preoperative PSA, pathological Gleason score, extraprostatic extension, seminal vesicle invasion, time to PCa BCR, PSA level at PCa BCR, and PSADT (all p < 0.05). Conclusions We constructed and validated a nomogram to predict the risk of PCSM at 10 yr among men with PCa BCR after radical prostatectomy. The nomogram may be used for patient counseling and the design of clinical trials for PCa. Patient summary For men with biochemical recurrence of prostate cancer after radical prostatectomy, we have developed a model to predict the long-term risk of death from prostate cancer.
To assess long-term prostate-specific antigen (PSA) outcome after permanent prostate brachytherapy (BT) and identify predictors of improved disease-free survival.
Eleven institutions combined data on ...2,693 patients treated with permanent interstitial BT monotherapy for T1-T2 prostate cancer. Of these patients, 1,831 (68%) were treated with I-125 (median dose, 144 Gy) and 862 (32%) were treated with Pd-103 (median dose, 130 Gy). Criteria for inclusion were: available pre-BT PSA, BT > or =5 years before data submission, BT between 1988-1998, and no androgen deprivation before failure. The median follow-up was 63 months.
Among patients where the I-125 dose to 90% of the prostate (D90) was > or =130 Gy, the 8-year PSA relapse-free survival (PRFS) was 93% compared with 76% for those with lower D90 dose levels (p < 0.001). A multivariable analysis identified tumor stage (p = 0.002), Gleason score (p < 0.001), pretreatment PSA level (p < 0.001), treatment year (p = 0.001), and the isotope used (p = 0.004) as pretreatment and treatment variables associated with PRFS. When restricted to patients with available postimplantation dosimetric information, D90 emerged as a significant predictor of biochemical outcome (p = 0.01), and isotope was not significant. The 8-year PRFS was 92%, 86%, 79%, and 67%, respectively, for patients with PSA nadir values of 0-0.49, 0.5-0.99, 1.0-1.99, and >2.0 ng/mL (p < 0.001). Among patients free of biochemical relapse at 8 years, the median nadir level was 0.1 ng/mL, and 90% of these patients achieved a nadir PSA level <0.6 ng/mL.
Outcome after permanent BT for prostatic cancer relates to tumor stage, Gleason score, pretreatment PSA, BT year, and post-BT dosimetric quality. PSA nadir < or =0.5 ng/mL was particularly associated with durable long-term PSA disease-free survival. The only controllable factor to impact on long-term outcome was the D90 which is a reflection of implant quality.
Skeletal-related events (SREs), which include radiation to the bone (RtB), can occur among patients with bone metastasis (BM). There is a recognized potential for misclassification of RtB when using ...claims data. We compared alternative measures of RtB to better understand their impact on SRE prevalence and SRE-related mortality.
We analyzed data for stage IV prostate cancer (PCa) cases identified between 2005 and 2009 in the Surveillance, Epidemiology, and End Results registry linked with Medicare claims. We created two measures of RtB: 1) a literature-based measure requiring the presence of a prior claim with a BM code; 2) a new measure requiring either that the BM code coincided with the radiation episode or that the duration of the radiation episode was less than or equal to 4 weeks. We estimated adjusted hazard ratios of an SRE using both measures among stratified samples: no metastasis (M0), metastasis to bone (M1b) and other sites (M1c).
The study sample included 5,074 men with stage IV PCa (median age 77 years), of whom 22% had M0, 54% had M1b, and 24% had M1c disease at time of PCa diagnosis. Based on Approaches 1 and 2, the proportion with probable RtB was 5% and 8% among M0, 30% and 30% among M1b, and 25% and 27% among M1c patients. Among M0 patients, the adjusted hazard ratio (AHR) associated with an SRE was 1.27 when using Approach 1 (95% confidence interval, CI: 0.95-1.7) and 1.49 when using Approach 2 (95% CI: 1.14-1.96). However, the impact of SREs on mortality did not differ between both approaches among M1b and M1c patients.
We found that alternative measures used to define RtB as SRE in claims data impact conclusions regarding the effect of SREs on mortality among M0 but not M1 patients.
We assessed the impact of cribriform pattern and/or intraductal carcinoma on Gleason 7 prostate cancer treated with external beam radiotherapy.
We evaluated men with Gleason 7 (Grade Groups 2 and 3) ...prostate cancer treated with dose escalated external beam radiotherapy with or without androgen deprivation. We reviewed biopsies for the presence of cribriform pattern and/or intraductal carcinoma. Study end points included biochemical recurrence-free, distant metastasis-free and disease specific survival.
In the 237 patients median followup was 117 months (range 3 to 236). According to National Comprehensive Cancer Network® risk groups 24% of patients were at favorable intermediate risk, 53% were at unfavorable intermediate risk and 23% were at high risk. The rate of cribriform pattern without intraductal carcinoma, cribriform pattern with intraductal carcinoma, intraductal carcinoma without cribriform pattern and none of these morphologies was 36%, 13%, 0% and 51%, respectively. On multivariable analysis cribriform pattern with intraductal carcinoma (HR 4.22, 95% CI 2.08-8.53, p <0.0001), prostate specific antigen 10 to 20 ng/ml (HR 1.97, 95% CI 1.03-3.79, p=0.04) and prostate specific antigen greater than 20 ng/ml (HR 2.26, 95% CI 1.21-4.23, p=0.01) were associated with worse biochemical recurrence-free survival. On multivariable analysis only cribriform pattern with intraductal carcinoma was associated with inferior distant metastasis-free survival (HR 4.18, 95% CI 1.43-12.28, p=0.01) and disease specific survival (HR 14.26, 95% CI 2.75-74.04, p=0.0016). Factors associated with cribriform pattern with or without intraductal carcinoma included Grade Group 3, high risk group and 50% or more positive biopsy cores. When stratified by neither morphology present, cribriform pattern without intraductal carcinoma and cribriform pattern with intraductal carcinoma the differences in biochemical recurrence-free, distant metastasis-free and disease specific survival were statistically significant (p=0.00042, p=0.017 and p <0.0001, respectively).
Cribriform pattern with intraductal carcinoma was associated with adverse outcomes in men with Gleason 7 prostate cancer treated with external beam radiotherapy while cribriform pattern without intraductal carcinoma was not so associated. Future studies may benefit from dichotomizing these 2 histological entities.
To determine clinical or dosimetric factors associated with a prostate-specific antigen (PSA) bounce, as well as an association between a PSA bounce and biochemical relapse-free survival (bRFS), in ...patients treated with iodine-125 brachytherapy.
A variety of clinical and treatment factors were examined in 820 patients who had a minimum of 3 years of PSA follow-up with T1-T2cN0M0 prostate cancer. Four different PSA threshold values were used for defining a PSA bounce: a PSA rise of ≥ 0.2, ≥ 0.4, ≥ 0.6, and ≥ 0.8 ng/mL.
A PSA bounce of ≥ 0.2, ≥ 0.4, ≥ 0.6, and ≥ 0.8 ng/mL was noted in 247 patients (30.1%), 161 (19.6%), 105 (12.8%), and 78 (9.5%), respectively. The median time to the first PSA rise was 17.4, 16.25, 16.23, and 15.71 months, respectively, vs. 34.35 months for a biochemical failure (p < 0.0001). A PSA rise of ≥ 0.2 ng/mL was the only definition for which there was a significant difference in bRFS between bounce and non-bounce patients. The 5-year bRFS rate of patients having a PSA bounce of ≥0.2 was 97.7% vs. 91% for those who did not have a PSA bounce (p = 0.0011). On univariate analysis for biochemical failure, age, risk group, and PSAs per year had a statistically significant correlation with PSA bounce of ≥ 0.2 ng/mL. On multivariate analysis, age and PSAs per year remained statistically significant (p < 0.0001 and p = 0.0456, respectively).
A bounce definition of a rise ≥ 0.2 ng/mL is a reliable definition among several other definitions. The time to first PSA rise is the most valuable factor for distinguishing between a bounce and biochemical failure.
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