available at http://www.ncbi.nlm.nih.gov/pubmed/28146658 Editorial Comment: In this study men with pT2-3,N0 radical prostatectomy pathology and a measurable postoperative prostate specific antigen were randomized to undergo salvage radiotherapy alone or in conjunction with 2 years of bicalutamide, a competitive androgen receptor inhibitor. Men receiving bicalutamide in addition to undergoing salvage radiotherapy had lower rates of metastatic progression and prostate cancer death at a median followup of 13 years. The analyses, although not specifically stipulated, appear to have been done on an intention to treat basis, meaning on the basis of randomization rather than whether the patient actually received the treatment. Regardless, it appears that adherence was comparable (at about 65%) between the antiandrogen and placebo arms, much to my surprise. It is noteworthy that this study was initiated in 1998, well after initiation of the EORTC (European Organization for Research and Treatment of Cancer) 22863 study, in which men were randomized to undergo primary radiotherapy with or without androgen deprivation by luteinizing hormonereleasing hormone (LHRH) agonist therapy for high risk prostate cancer but well before its final results were published. As such, the rationale for using antiandrogen therapy instead of LHRH agonists is unclear but appears to have been entirely hypothesis driven at trial conception. The fact that the results show an effect perhaps comparable to LHRH agonists is appealing in several respects. In general antiandrogens are more tolerable than pharmacological castration, with preservation of libido and sexual function in some men due to continued normal to high testosterone levels. Additionally antiandrogens are short acting and easily reversed, allowing tighter control of the period of castration than traditional LHRH agonists. Reluctance to administer adjuvant and salvage therapies, such as radiation and/or androgen deprivation, generally relates to a concern regarding the impact on recovery of urinary and sexual function. In this study the authors do not provide data regarding the impact of therapy on functional outcomes and do not comment on the influence of antiandrogens on sexual functional recovery. While the impact on mortality should not be ignored, it is important to realize that cancer specific mortality in men with biochemical relapse following surgery is quite low overall. In this study the benefit of adding bicalutamide was greatest in men with aggressive disease features. As such, to make combined radiation and androgen deprivation palatable as a salvage strategy, the effects on functional 0022-5347/17/1981-0100/0 THE JOURNAL OF UROLOGY 2017 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. http://dx.doi.org/10.1016/j.juro.2017.04.048 Vol. 198, 100-106, July 2017 Printed in U.S.A.

We published a scoring algorithm to predict biochemical failure (BCF) following salvage radiation therapy (SRT) for postoperative elevation of serum prostate-specific antigen (PSA) in prostate cancer (PCa). While this algorithm has demonstrable clinical value, it is based entirely on clinico-pathologic features and does not incorporate information from tumor-based biomarkers. Identification of biomarkers within primary tumor tissue that correlate with BCF following SRT may enhance outcome prediction, inform on the biology of PCa aggressiveness, and provide rationale targets for adjuvant therapy. Herein, we evaluate the ability of Ki-67 expression in primary PCa to aid prediction of BCF in a cohort of men undergoing SRT. We identified 148 patients treated with SRT between July 1987 and July 2003 at Mayo Clinic and had archived prostatectomy tissue available for immunohistochemical analysis. Expression levels of Ki-67 in primary tumor samples were detected using a monoclonal antibody (Clone: Mib-1; Dako Corp., Carpinteria, CA) and quantified as a Mean Index Percentage using image analysis Automated Cellular Imaging System (ACIS, Clarient Inc., San Juan Capistrano, CA). Clinical, pathologic and follow-up data on these patients were abstracted from our SRT Database. We used Cox proportional hazards regression analysis to examine the association of Ki-67 expression and BCF in single variable models and after adjustment for other variables. There was evidence of a higher risk of BCF with an increasing Ki-67 expression level (p = 0.003). We estimated that men with tumors in the highest tertile of Ki-67 expression are over two times more likely to experience BCF compared to men with tumors in lowest tertile [Relative risk (RR) = 2.45; 95% confidence interval (CI) 1.33 - 4.50]. Adjustment for the covariates (pathological tumor stage, Gleason score, pre-radiotherapy PSA) in our original scoring system did not attenuate the association (p = 0.003; RR = 3.04; 95% CI 1.59 - 5.81). Our data are the first to indicate that Ki-67 expression enhances the prediction of outcome for men undergoing SRT post-prostatectomy. Ki-67 staining should be considered in protocol stratification and outcome models.

Results:Significant variation in the definitionof the CTV was seen.The minimum,maximum, mean(SD) volumes(cc) were 23.5, 281.6, 88.5±74.8 for case 1 and 31.8, 434.7, 159.5± 116.6for case 2. The volume of 100% agreement was 6.8 and 13.4 for case 1 and 2 and the volume of the union of all contours was 322.7 and 547.6 for case 1 and 2, respectively. The overall agreement was judged to be moderate in both cases (kappa = 0.41 (p\0.0001) and kappa = 0.42 (p\0.0001), respectively. The estimated experts’ sensitivities and specificities were 0.5 ±0.25 and 0.99± 0.03 for case 1 and 0.62± 0.22 and 0.96± 0.07 for case 2 indicating higher agreement levels with increased volumes as shown in Figure 1. The questionnaires confirmed the defined variations. For example: the range of definitions for the inferior border of the CTV went from the bottom of the ischial tuberosities to the apex of a urethrogram. Likewise the lateral borders ranged from 5 to 10 cm in width. Conclusions:Significant disagreement exists in the definition of the CTV for postoperative prostate radiation therapyamongst GU specialists. A consensus for a future trials employing conformal or IMRT techniques needs to be developed to be sure that targets are treated adequately. This work was supported by NIH U24 grant CA81647, ‘‘Advanced Technology QA Center’’. Fleiss, J. L. (1981) Statistical methods for rates and proportions, New York, Wiley. Warfield, S. K., Zou, K. H. & Wells, W. M. (2004) Simultaneous truth and performance level estimation (STAPLE): an algorithm for the validation of image segmentation. IEEE Trans Med Imaging, 23, 903‐21.

The majority of breast cancers (BC) in Nigerian women are triple negative and show breast cancer-associated gene 1 (BRCA1) deficiency as well as the basal like phenotype, with a high mortality rate. In contrast to the well-defined predictive factors for the hormonal therapy, there is a paucity of information on the BRCA1 deficiency breast tumor biology, particularly among African women. BRCA1 Sumoylation (UBC9) has been speculated to be involved in the ER transcription activity, BRCA1 deficiency and triple negative BC. We therefore hypothesized that UBC9, a SUMOylation marker, may have contributed to the aggressive nature of BRCA1 tumor phenotype observed in Nigerian women.This study investigated the immunoprofiles of UBC9 in tissue microarray (TMA) of 199 Nigerian women and correlated their protein expression with clinical outcome, pathological responses and the expression of other biomarkers to demonstrate the functional significance in Nigerian women.The protein expression of UBC9, as compared with other biomarkers, showed an inverse correlation with steroid hormones (ER, progesterone (PgR)), BRCA1, p27, p21 and MDM4, and a positive correlation with triple negative, basal cytokeratins (CK14 and CK5/6), epidermal growth factor receptor (EGFR), basal-like breast cancer phenotype, p53, phosphoinositide-3-kinases (PI3KCA), placental cadherin, (P-cadherin) and BRCA1 regulators (metastasis tumor antigen-1 (MTA1). Survival analysis showed that those tumors positive for UBC9 expression had a significantly poorer breast cancer-specific survival (BCSS) as compared with those showing negative expression. UBC9 remained an independent predictor of outcome for BCSS.This study demonstrates that UBC9 appears to play an important role in the tumor biology of Nigerian women. Therefore, a novel UBC9 targeted therapy in black women with BC could enhance a better patient outcome.

You have accessJournal of UrologyPodium, Sunday, May 22, 2005, 1:00 - 3:00 pm1 Apr 2005472: Predictors of Biochemical Relapse Following Salvage Radiation Therapy for Recurrent Prostate Cancer Alexander S. Parker, Steven Buskirk, Michael G. Heckman, Tim Pisansky, Karen A. Prussak, Michael Wehle, Robert G. Ferrigni, Steven E. Schild, and Robert P. Myers Alexander S. ParkerAlexander S. Parker More articles by this author , Steven BuskirkSteven Buskirk More articles by this author , Michael G. HeckmanMichael G. Heckman More articles by this author , Tim PisanskyTim Pisansky More articles by this author , Karen A. PrussakKaren A. Prussak More articles by this author , Michael WehleMichael Wehle More articles by this author , Robert G. FerrigniRobert G. Ferrigni More articles by this author , Steven E. SchildSteven E. Schild More articles by this author , and Robert P. MyersRobert P. Myers More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)34725-6AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "472: Predictors of Biochemical Relapse Following Salvage Radiation Therapy for Recurrent Prostate Cancer." The Journal of Urology, 173(4S), p. 129 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 173Issue 4SApril 2005Page: 129 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Alexander S. Parker More articles by this author Steven Buskirk More articles by this author Michael G. Heckman More articles by this author Tim Pisansky More articles by this author Karen A. Prussak More articles by this author Michael Wehle More articles by this author Robert G. Ferrigni More articles by this author Steven E. Schild More articles by this author Robert P. Myers More articles by this author Expand All Advertisement PDF DownloadLoading ...

Purpose: To compare long-term outcome using alternative failure definitions after external beam radiation for localized prostate cancer.Methods and Materials: Data from 4839 patients with stage T1b, T1c, and T2 adenocarcinoma of the prostate who were treated solely with external beam radiation between 1986 and 1995 at nine U.S. institutions were analyzed. Outcome using the following prostate-specific antigen (PSA) failure definitions was compared: (1) three consecutive PSA rises backdated (American Society for Therapeutic Radiology and Oncology [ASTRO]), (2) two PSA rises of at least 0.5 ng/mL each, backdated (0.5 x 2), (3) three consecutive PSA rises with failure recorded at the call date (ASTRO call date), (4) PSA greater than or equal tocurrent PSA nadir + 2 ng/mL (Houston + 2), (5) PSA greater than or equal tocurrent PSA nadir + 3 ng/mL (Houston + 3), (6) PSA >0.2 ng/mL, or (7) PSA >0.5 ng/mL. For definitions 3-7, the failure date was recorded as the date the criterion was met, without backdating.Results: PSA disease-free survival (PSA-DFS) varied according to the failure definition used with differences of up to 13% with PSA rise definitions and up to 44% with absolute nadir value surgical-type definitions within the first 5 years post-therapy as compared with the ASTRO definition. PSA-DFS was 66%, 66%, 68%, 72%, 15%, and 25% at 5 years postradiation for definitions 2-7, respectively, vs. 59% for the ASTRO definition. Sensitivity and specificity of definitions 2, 4, and 5 were better than for the ASTRO definition, whereas, for definitions 6 and 7, the sensitivity was at least 90% but the specificity was only 9% and 26%, respectively. This analysis shows that the ASTRO definition does not overestimate outcome, particularly in the first 5 years after therapy, as compared with other definitions appropriate to irradiated patients.Conclusion: There are notable differences in both short- and long-term outcomes after definitive radiation for prostate cancer depending on the failure definition applied. Failure definitions must be tested objectively for sensitivity and specificity in predicting clinical outcome, and it is only in this manner that reasonable choices can be made. Although traditional surgical-type failure definitions do not seem applicable to patients treated with external beam radiation, further analysis of definitions across multiple therapeutic modalities is necessary to determine whether a universal failure definition might be feasible, at least for research and comparative purposes. (C) 2005 Elsevier Inc.

Purpose/Objective: To assess long-term prostate-specific antigen (PSA) outcome after permanent prostate brachytherapy (BT) and compare differences based on the failure definitions applied.Materials/Methods: Eleven institutions combined data on 2693 patients (pts) treated with permanent interstitial BT monotherapy for T1–T2 prostate cancer. 1831 pts (68%) were treated with I-125 (median dose: 160 Gy) and 862 pts (32%) were treated with Pd-103 (median dose: 120 Gy). Criteria for inclusion were: available pre-BT PSA, BT > 5 years before data collection, BT between 1988 -1998, and no prior androgen deprivation. The median follow-up is 63 months. Prognostic risk groups were defined according to the National Comprehensive Cancer Network. Based on an analysis of PSA failure definitions for BT pts (Kuban et al), 2 definitions were more sensitive/specific and had a better regression analysis fit than the ASTRO definition. Thus, nadir +1 ng/ml and nadir +2 ng/ml were also used.Results: 8-year PSA-DFS rates were 73%, 60% and 41% for low, intermediate and high risk I-125 pts, respectively, and 73%, 64%, and 38% for Pd-103 pts respectively, using the nadir +2 definition. D90 >140 Gy, compared to lower doses, was a significant predictor for improved 8-yr PSA-DFS for I-125 pts (90% vs 73%; p < 0.001) using the nadir +2 definition. Multivariable analysis identified the following as predictors for improved PSA-DFS: tumor stage (p < 0.001), Gleason score (p< 0.001), pre-BT PSA (p< 0.001), BT year (p=0.001) and D90 (p=0.009) as a percent of the prescribed dose. As a post-BT variable, PSA nadir value 3 yrs after BT was a significant predictor irrespective of the failure definition applied (p=0.0001). Among pts treated with I-125 and Pd-103 who achieved a PSA nadir < 0.5 by 3 yrs, the 8-yr PSA-DFS (nadir +2 definition) was 89% and 85% for I-125 and Pd-103 pts, respectively. Among patients who were free of biochemical relapse at 8 years (nadir+2 definition) the median nadir level was 0.1 ng/ml, and 90% of these patients achieved a nadir PSA level <0.6 ng/ml. As compared to the nadir +2 definition, the ASTRO definition was associated with an approximately 7% lower PSA failure rate for each risk group, and the nadir +1 definition was associated with an approximately 7% higher failure rate for each group.Conclusions: Outcome after permanent BT for prostatic cancer depends on tumor stage, Gleason score, pretreatment PSA, BT year, and post-BT dosimetric quality. PSA nadir < 0.5 ng/ml was associated with durable long-term PSA-DFS. The only controllable factor to impact on long-term outcome remains the D90 which is a reflection of implant quality. Further studies will need to control for implant quality when reporting long-term outcome after BT for prostate cancer. Purpose/Objective: To assess long-term prostate-specific antigen (PSA) outcome after permanent prostate brachytherapy (BT) and compare differences based on the failure definitions applied. Materials/Methods: Eleven institutions combined data on 2693 patients (pts) treated with permanent interstitial BT monotherapy for T1–T2 prostate cancer. 1831 pts (68%) were treated with I-125 (median dose: 160 Gy) and 862 pts (32%) were treated with Pd-103 (median dose: 120 Gy). Criteria for inclusion were: available pre-BT PSA, BT > 5 years before data collection, BT between 1988 -1998, and no prior androgen deprivation. The median follow-up is 63 months. Prognostic risk groups were defined according to the National Comprehensive Cancer Network. Based on an analysis of PSA failure definitions for BT pts (Kuban et al), 2 definitions were more sensitive/specific and had a better regression analysis fit than the ASTRO definition. Thus, nadir +1 ng/ml and nadir +2 ng/ml were also used. Results: 8-year PSA-DFS rates were 73%, 60% and 41% for low, intermediate and high risk I-125 pts, respectively, and 73%, 64%, and 38% for Pd-103 pts respectively, using the nadir +2 definition. D90 >140 Gy, compared to lower doses, was a significant predictor for improved 8-yr PSA-DFS for I-125 pts (90% vs 73%; p < 0.001) using the nadir +2 definition. Multivariable analysis identified the following as predictors for improved PSA-DFS: tumor stage (p < 0.001), Gleason score (p< 0.001), pre-BT PSA (p< 0.001), BT year (p=0.001) and D90 (p=0.009) as a percent of the prescribed dose. As a post-BT variable, PSA nadir value 3 yrs after BT was a significant predictor irrespective of the failure definition applied (p=0.0001). Among pts treated with I-125 and Pd-103 who achieved a PSA nadir < 0.5 by 3 yrs, the 8-yr PSA-DFS (nadir +2 definition) was 89% and 85% for I-125 and Pd-103 pts, respectively. Among patients who were free of biochemical relapse at 8 years (nadir+2 definition) the median nadir level was 0.1 ng/ml, and 90% of these patients achieved a nadir PSA level <0.6 ng/ml. As compared to the nadir +2 definition, the ASTRO definition was associated with an approximately 7% lower PSA failure rate for each risk group, and the nadir +1 definition was associated with an approximately 7% higher failure rate for each group. Conclusions: Outcome after permanent BT for prostatic cancer depends on tumor stage, Gleason score, pretreatment PSA, BT year, and post-BT dosimetric quality. PSA nadir < 0.5 ng/ml was associated with durable long-term PSA-DFS. The only controllable factor to impact on long-term outcome remains the D90 which is a reflection of implant quality. Further studies will need to control for implant quality when reporting long-term outcome after BT for prostate cancer.

Purpose/Objective: One of the goals of PBRT is to minimize dose to the unaffected breast tissue while delivering an intended, high dose to the target area. The purpose of this study is to examine the effect of location and size of PTV on DVH of the breast in external beam PBRT. Materials/Methods: A normal, unaffected, left breast of a breast cancer patient was selected for this study. CT images of the breast were obtained with 2.5 mm thickness per slice. The breast volume (BV) was calculated, using the following boundaries (medial: mid-sternum; lateral: mid-axilla; superior: sternal notch; inferior: 2 cm below the infra-mammary crease; anterior: skin; posterior: chest wall outlined by anterior aspect of the ribs), and measured 1490 cm3. The current NSABP clinical study protocol (B-39) was used to guide the construction of beam arrangements. Using the location of PTV and % PTV/BV as variables, we generated DVHs of the breast for 5 different locations (central, UOQ, UIQ, LOQ, and LIQ). The model included 5, 10, 15, 20, and 25% PTV/BV, which correspond to maximum PTV diameters of 5.5, 7.2, 8.5, 9.9, and 10.5 cm. Results: Table shows the % of BV receiving 10–100% of prescription (Rx) for a centrally located PTV. Data was also obtained for the other 4 locations of PTV with varying %PTV/BV (not shown). % of Rx (%Rx) are plotted as a function of %PTV/BV and location (e.g. Graph for %PTV/BV= 5% and 25%). The following observations are made: 1. When %PTV/BV= 25%, 49–76% and 59–88% of the breast received 50%Rx and 20%Rx depending on location of PTV. This means that when the Rx for PTV is 3850 cGy, 59–88% of the breast volume received 770 cGy. A question can be raised as to the long term safety of this low to intermediate radiation dose. 2. The smaller %PTV/BV, less effect is seen of PTV location on the volume of breast receiving over 50%Rx. 3. At a given %PTV/BV, the volume of breast receiving lower dose of radiation (e.g. 10%Rx) became more dependant on PTV location. 4. At any given %PTV/BV, PTV located in the UIQ had the largest % of breast treated above 50%Rx due to beam arrangement limitations per NSABP protocol on the contralateral breast, heart, and lung. In contrast, PTV located in the LOQ gives the smallest % of breast volume treated above 50%Rx as it allows more options for beam arrangement. Conclusions: A significant proportion of the breast receives a low to intermediate radiation dose in PBRT, and its extent is dependent on location and size of PTV. Tabled 1

This prospective trial was opened by the Radiation Therapy Oncology Group (RTOG) in 1998 to evaluate the effectiveness of transrectal ultrasound guided permanent implantation of the prostate compared to historical data of prostatectomy or external beam radiotherapy within a cooperative group setting with special attention to the quality assurance standards of brachytherapy. One hundred and one patients were accrued to this protocol, which closed in April 2000. Accrued patients had low risk prostate cancer (T1-2, GS<6, PSA <10) and underwent an I125 permanent implantation of the prostate (145 Gy TG-43). Of 101 patients, 97 are eligible and analyzable. Of the eligible patients, 96 had brachytherapy data and 95 had adequate follow up for evaluation. Median follow up was 41 months (range 4.5 months to 60.1 months). Ninety-four of the eligible patients had an implant that was delivered either per protocol or with an acceptable minor variation. The 3-year cumulative incidence rate of any failure is 9.8% per the protocol definition of failure (two consecutive rises above the nadir with the rise in PSA exceeding 1 ng/ml above the nadir or positive biopsy). The 3-year biochemical failure rates using the protocol definition and the ASTRO definition were 4.3% and 3.2% respectively. Acute grade 3 or higher toxicity was seen in eight patients, four of the eight were GU toxicity, 2 sexual, and the others hemorrhage. There were no grade 4 or grade 5 acute toxicities. Fifty patients experienced grade 2 toxicity, 44 of the 50 were genitourinary toxicities. Late grade 3 or higher toxicity was noted in 2 patients with grade 3 toxicity both genitourinary and no grade 4 or grade 5 toxicity. This prospective multi-institutional brachytherapy trial was completed successfully with acceptable quality assurance and early results comparable with single institution series. The toxicities are consistent with other reported series. With this trial, the RTOG has demonstrated its capacity to perform a prospective quality assured prostate brachytherapy trial and provides a positive outlook for the feasibility of subsequent cooperative group trials, including the active Phase III trial RTOG P-0232 examining the role of supplemental external beam radiotherapy for prostate brachytherapy

To evaluate the results and prognostic factors associated with radiotherapy (RT) for a detectable prostate specific antigen (PSA) level after radical prostatectomy (RP). From July 1987 through July 2003, 368 patients received RT for a detectable PSA level (biochemical relapse {BCR}) as sole evidence of recurrence after RP for node negative prostate cancer. The following variables were assessed with respect to their association with biochemical relapse and survival: age, pathologic tumor stage, tumor grade, Gleason score (GS), margin status, DNA ploidy, pre-RP PSA, pre-RT PSA, pre-RT PSA doubling time, RT dose and pre-RT hormone therapy. Biochemical relapse was defined as a single post-RT value ≥0.4 ng/ml and not declining. Estimated survival and relapse-free probabilities were obtained via Kaplan-Meier estimation. Associations of patient factors with time until death and time until biochemical relapse were investigated using log-rank tests. Cox proportional hazards models with forward selection were used to investigate which variables showed evidence independent associations. With a median follow-up of 5 years, the 5 and 10-year freedom from BCR and survival for the entire cohort were an estimated 46% (95% CI: 41%-52%) and 30% (95% CI: 21%-37%) and 92% (95% CI: 89%-95%) and 76% (95% CI: 68%-83%). Patient and treatment variables showing evidence of association with biochemical relapse included: pathologic stage; ≤T3a vs. T3b, (p = 0.002); pathologic GS ≤7 vs. ≥8; (p < 0.001); Broders’ grade 1, 2 vs. 3, 4; (p = 0.01); pre-RT PSA; <1.0 vs. ≥1.0 (p < 0.001); pre-op PSA <15 vs. ≥15 (p = 0.01), RT dose; ≤64.8 vs. >64.8 Gy (p < 0.001); DNA ploidy: diploid vs. non-diploid (p = 0.004) and pre-RT PSA doubling time; <7.5 vs. ≥7.5 months (p = 0.001). Forward selection of variables indicated that pathologic stage, Gleason score and pre-radiotherapy PSA were the only variables showing clear evidence of independent associations. Others no longer showed evidence of association after adjusting for these three variables. Variables showing evidence of association with patient survival were: pathologic stage ≤ T3a vs. T3b, (p = 0.005), Broders’ grade 1, 2 vs. 3, 4 (p = 0.001) and DNA ploidy: diploid vs. non-diploid (p = 0.02). Forward selection of variables indicated that Broders’ grade was the only variable showing evidence of an association independent of the other variables considered. Exploratory analysis indicated that of patients with pathologic stage ≤T3a, Gleason score ≤7 and a pre-radiotherapy PSA <1.0 (low-risk category), approximately 50% had freedom from biochemical failure at 10 years versus approximately 20% for other patients. The presence of seminal vesicle invasion and high GS in the RP specimen are inherent predictors of adverse outcome. Higher pre-RT PSA levels also lead to a worse outcome after RT, but the influence of this factor can be mitigated through patterns of referral with early introduction of salvage RT. One half of patients with a combination of low-risk features may be expected to be free of a second BCR 10 years after salvage RT

Purpose/ObjectiveTo predict outcome in patients failing biochemically after radiation for prostate cancer and to determine which patients may benefit most from additional therapy.Materials/Methods4839 patients with stage T1b-T2 prostatic carcinoma treated with external beam radiation alone at 9 U.S. institutions in the PSA era were analyzed. Patients were treated to a dose of at least 60 Gy from 1986–1995 with a median follow-up of 6.3 years. 1421 patients had a biochemical failure (PSAF), as the first event, by ASTRO criteria and had subsequent follow-up information. 895 patients had no hormonal therapy (HT) for the entire duration of follow-up or until the development of distant metastasis (DM) and 526 patients were hormonally treated. The Wilcoxon sum test was used to compare the standard pretreatment prognostic variables as well as PSA doubling time after radiation (PSADT) and the interval from treatment to PSA failure (iPSA) for patients who were and were not treated with HT before DM. Multivariate analysis was done for the clinical endpoint of distant metastasis. Recursive partitioning analysis (RPA) was used to determine the most significant factors and cutpoints for distant failure. Kaplan Meier analyses for distant metastasis-free survival (DMFS) and cause-specific survival (CSS) were performed for the 3 most significant prognostic factors, Gleason score, PSADT, and iPSAF. The log rank test compared differences between groups.ResultsThere were 92 distant failures in the 895 patients who did not have HT before distant failure with a DMFS of 86% at 5 years and 83% at 8 years. There was a significant difference in DMFS based on Gleason score(2–5, 6, 7, and 8–10 = 89%, 82%, 80%, and 65%, respectively), PSADT (>10 months vs <10 months, 88% vs 65%) and iPSAF (>2years vs <2 years, 85% vs 57%) at 8 years after biochemical failure, p < .0001 for all 3 factors. PSADT and iPSAF were the most significant combination in predicting DMFS after PSAF. DMFS was 82% at 8 years for PSADT >10 months and iPSAF >2 years even if the Gleason score was 8–10. Conversely, with PSADT <10 months and iPSAF <2 years, DMFS was 46% with no advantage for lower Gleason score tumors. Patients with higher Gleason scores pretreatment were those most likely to fall into this poor prognostic category post-irradiation. In RPA analysis, patients with a PSADT ≤4 months and an iPSAF ≤2 years had a risk of DM 47 times higher than patients with a DT >9 months.The 526 patients who were treated with HT prior to DM had significantly more aggressive pretreatment prognostic variables as well as significantly shorter PSADTs and iPSAFs as compared to patients who did not have HT. HT was initiated at a median of 1.1 years after PSAF. In RPA analysis, the 2 most significant factors for DM were PSADT and Gleason score. Patients with a pre-HT PSADT ≤6 months and a Gleason score ≥7 had a risk of DM 8 times higher than patients with a PSADT >6 months.In comparing patients who were and were not treated with HT before DM, those in the worst prognostic group(PSADT ≤4 months) had DMFS of 78% versus 35% at 5 years, respectively, and those with a PSADT >10 months had DMFS which was similar, 88–89%, regardless of the administration of HT. CSS showed the same striking differences, and even more so when iPSAF was factored in.ConclusionsOutcome after PSAF following external beam radiation varies significantly and is dependent most on PSADT and iPSAF. Patients with a short PSADT and iPSAF (<10 months and <2 years, respectively) are those who seem to benefit most from HT. For those with a PSADT ≤6 months and Gleason score ≥7, even more aggressive salvage therapy addressing distant disease is necessary Purpose/ObjectiveTo predict outcome in patients failing biochemically after radiation for prostate cancer and to determine which patients may benefit most from additional therapy. To predict outcome in patients failing biochemically after radiation for prostate cancer and to determine which patients may benefit most from additional therapy. Materials/Methods4839 patients with stage T1b-T2 prostatic carcinoma treated with external beam radiation alone at 9 U.S. institutions in the PSA era were analyzed. Patients were treated to a dose of at least 60 Gy from 1986–1995 with a median follow-up of 6.3 years. 1421 patients had a biochemical failure (PSAF), as the first event, by ASTRO criteria and had subsequent follow-up information. 895 patients had no hormonal therapy (HT) for the entire duration of follow-up or until the development of distant metastasis (DM) and 526 patients were hormonally treated. The Wilcoxon sum test was used to compare the standard pretreatment prognostic variables as well as PSA doubling time after radiation (PSADT) and the interval from treatment to PSA failure (iPSA) for patients who were and were not treated with HT before DM. Multivariate analysis was done for the clinical endpoint of distant metastasis. Recursive partitioning analysis (RPA) was used to determine the most significant factors and cutpoints for distant failure. Kaplan Meier analyses for distant metastasis-free survival (DMFS) and cause-specific survival (CSS) were performed for the 3 most significant prognostic factors, Gleason score, PSADT, and iPSAF. The log rank test compared differences between groups. 4839 patients with stage T1b-T2 prostatic carcinoma treated with external beam radiation alone at 9 U.S. institutions in the PSA era were analyzed. Patients were treated to a dose of at least 60 Gy from 1986–1995 with a median follow-up of 6.3 years. 1421 patients had a biochemical failure (PSAF), as the first event, by ASTRO criteria and had subsequent follow-up information. 895 patients had no hormonal therapy (HT) for the entire duration of follow-up or until the development of distant metastasis (DM) and 526 patients were hormonally treated. The Wilcoxon sum test was used to compare the standard pretreatment prognostic variables as well as PSA doubling time after radiation (PSADT) and the interval from treatment to PSA failure (iPSA) for patients who were and were not treated with HT before DM. Multivariate analysis was done for the clinical endpoint of distant metastasis. Recursive partitioning analysis (RPA) was used to determine the most significant factors and cutpoints for distant failure. Kaplan Meier analyses for distant metastasis-free survival (DMFS) and cause-specific survival (CSS) were performed for the 3 most significant prognostic factors, Gleason score, PSADT, and iPSAF. The log rank test compared differences between groups. ResultsThere were 92 distant failures in the 895 patients who did not have HT before distant failure with a DMFS of 86% at 5 years and 83% at 8 years. There was a significant difference in DMFS based on Gleason score(2–5, 6, 7, and 8–10 = 89%, 82%, 80%, and 65%, respectively), PSADT (>10 months vs <10 months, 88% vs 65%) and iPSAF (>2years vs <2 years, 85% vs 57%) at 8 years after biochemical failure, p < .0001 for all 3 factors. PSADT and iPSAF were the most significant combination in predicting DMFS after PSAF. DMFS was 82% at 8 years for PSADT >10 months and iPSAF >2 years even if the Gleason score was 8–10. Conversely, with PSADT <10 months and iPSAF <2 years, DMFS was 46% with no advantage for lower Gleason score tumors. Patients with higher Gleason scores pretreatment were those most likely to fall into this poor prognostic category post-irradiation. In RPA analysis, patients with a PSADT ≤4 months and an iPSAF ≤2 years had a risk of DM 47 times higher than patients with a DT >9 months.The 526 patients who were treated with HT prior to DM had significantly more aggressive pretreatment prognostic variables as well as significantly shorter PSADTs and iPSAFs as compared to patients who did not have HT. HT was initiated at a median of 1.1 years after PSAF. In RPA analysis, the 2 most significant factors for DM were PSADT and Gleason score. Patients with a pre-HT PSADT ≤6 months and a Gleason score ≥7 had a risk of DM 8 times higher than patients with a PSADT >6 months.In comparing patients who were and were not treated with HT before DM, those in the worst prognostic group(PSADT ≤4 months) had DMFS of 78% versus 35% at 5 years, respectively, and those with a PSADT >10 months had DMFS which was similar, 88–89%, regardless of the administration of HT. CSS showed the same striking differences, and even more so when iPSAF was factored in. There were 92 distant failures in the 895 patients who did not have HT before distant failure with a DMFS of 86% at 5 years and 83% at 8 years. There was a significant difference in DMFS based on Gleason score(2–5, 6, 7, and 8–10 = 89%, 82%, 80%, and 65%, respectively), PSADT (>10 months vs <10 months, 88% vs 65%) and iPSAF (>2years vs <2 years, 85% vs 57%) at 8 years after biochemical failure, p < .0001 for all 3 factors. PSADT and iPSAF were the most significant combination in predicting DMFS after PSAF. DMFS was 82% at 8 years for PSADT >10 months and iPSAF >2 years even if the Gleason score was 8–10. Conversely, with PSADT <10 months and iPSAF <2 years, DMFS was 46% with no advantage for lower Gleason score tumors. Patients with higher Gleason scores pretreatment were those most likely to fall into this poor prognostic category post-irradiation. In RPA analysis, patients with a PSADT ≤4 months and an iPSAF ≤2 years had a risk of DM 47 times higher than patients with a DT >9 months. The 526 patients who were treated with HT prior to DM had significantly more aggressive pretreatment prognostic variables as well as significantly shorter PSADTs and iPSAFs as compared to patients who did not have HT. HT was initiated at a median of 1.1 years after PSAF. In RPA analysis, the 2 most significant factors for DM were PSADT and Gleason score. Patients with a pre-HT PSADT ≤6 months and a Gleason score ≥7 had a risk of DM 8 times higher than patients with a PSADT >6 months. In comparing patients who were and were not treated with HT before DM, those in the worst prognostic group(PSADT ≤4 months) had DMFS of 78% versus 35% at 5 years, respectively, and those with a PSADT >10 months had DMFS which was similar, 88–89%, regardless of the administration of HT. CSS showed the same striking differences, and even more so when iPSAF was factored in. ConclusionsOutcome after PSAF following external beam radiation varies significantly and is dependent most on PSADT and iPSAF. Patients with a short PSADT and iPSAF (<10 months and <2 years, respectively) are those who seem to benefit most from HT. For those with a PSADT ≤6 months and Gleason score ≥7, even more aggressive salvage therapy addressing distant disease is necessary Outcome after PSAF following external beam radiation varies significantly and is dependent most on PSADT and iPSAF. Patients with a short PSADT and iPSAF (<10 months and <2 years, respectively) are those who seem to benefit most from HT. For those with a PSADT ≤6 months and Gleason score ≥7, even more aggressive salvage therapy addressing distant disease is necessary