Elizabeth B. Humphreys

Risk of Prostate Cancer–Specific Mortality Following Biochemical Recurrence After Radical Prostatectomy

ContextThe natural history of biochemical recurrence after radical prostatectomy can be long but variable. Better risk assessment models are needed to identify men who are at high risk for prostate cancer death early and who may benefit from aggressive salvage treatment and to identify men who are at low risk for prostate cancer death and can be safely observed.ObjectivesTo define risk factors for prostate cancer death following radical prostatectomy and to develop tables to risk stratify for prostate cancer–specific survival.Design, Setting, and PatientsRetrospective cohort study of 379 men who had undergone radical prostatectomy at an urban tertiary care hospital between 1982 and 2000 and who had a biochemical recurrence and after biochemical failure had at least 2 prostate-specific antigen (PSA) values at least 3 months apart in order to calculate PSA doubling time (PSADT). The mean (SD) follow-up after surgery was 10.3 (4.7) years and median follow-up was 10 years (range, 1-20 years).Main Outcome MeasureProstate cancer–specific mortality.ResultsMedian survival had not been reached after 16 years of follow-up after biochemical recurrence. Prostate-specific doubling time (<3.0 vs 3.0-8.9 vs 9.0-14.9 vs ≥15.0 months), pathological Gleason score (≤7 vs 8-10), and time from surgery to biochemical recurrence (≤3 vs >3 years) were all significant risk factors for time to prostate-specific mortality. Using these 3 variables, tables were constructed to estimate the risk of prostate cancer–specific survival at year 15 after biochemical recurrence.ConclusionClinical parameters (PSADT, pathological Gleason score, and time from surgery to biochemical recurrence) can help risk stratify patients for prostate cancer–specific mortality following biochemical recurrence after radical prostatectomy. These preliminary findings may serve as useful guides to patients and their physicians to identify patients at high risk for prostate cancer–specific mortality following biochemical recurrence after radical prostatectomy to enroll them in early aggressive treatment trials. In addition, these preliminary findings highlight that survival in low-risk patients can be quite prolonged.

Prostate Cancer-Specific Survival Following Salvage Radiotherapy vs Observation in Men With Biochemical Recurrence After Radical Prostatectomy

CONTEXT Biochemical disease recurrence after radical prostatectomy often prompts salvage radiotherapy, but no studies to date have had sufficient numbers of patients or follow-up to determine whether radiotherapy improves survival, and if so, the subgroup of men most likely to benefit. OBJECTIVES To quantify the relative improvement in prostate cancer-specific survival of salvage radiotherapy vs no therapy after biochemical recurrence following prostatectomy, and to identify subgroups for whom salvage treatment is most beneficial. DESIGN, SETTING, AND PATIENTS Retrospective analysis of a cohort of 635 US men undergoing prostatectomy from 1982-2004, followed up through December 28, 2007, who experienced biochemical and/or local recurrence and received no salvage treatment (n = 397), salvage radiotherapy alone (n = 160), or salvage radiotherapy combined with hormonal therapy (n = 78). MAIN OUTCOME MEASURE Prostate cancer-specific survival defined from time of recurrence until death from disease. RESULTS With a median follow-up of 6 years after recurrence and 9 years after prostatectomy, 116 men (18%) died from prostate cancer, including 89 (22%) who received no salvage treatment, 18 (11%) who received salvage radiotherapy alone, and 9 (12%) who received salvage radiotherapy and hormonal therapy. Salvage radiotherapy alone was associated with a significant 3-fold increase in prostate cancer-specific survival relative to those who received no salvage treatment (hazard ratio [HR], 0.32 [95% confidence interval {CI}, 0.19-0.54]; P<.001). Addition of hormonal therapy to salvage radiotherapy was not associated with any additional increase in prostate cancer-specific survival (HR, 0.34 [95% CI, 0.17-0.69]; P = .003). The increase in prostate cancer-specific survival associated with salvage radiotherapy was limited to men with a prostate-specific antigen doubling time of less than 6 months and remained after adjustment for pathological stage and other established prognostic factors. Salvage radiotherapy initiated more than 2 years after recurrence provided no significant increase in prostate cancer-specific survival. Men whose prostate-specific antigen level never became undetectable after salvage radiotherapy did not experience a significant increase in prostate cancer-specific survival. Salvage radiotherapy also was associated with a significant increase in overall survival. CONCLUSIONS Salvage radiotherapy administered within 2 years of biochemical recurrence was associated with a significant increase in prostate cancer-specific survival among men with a prostate-specific antigen doubling time of less than 6 months, independent of other prognostic features such as pathological stage or Gleason score. These preliminary findings should be validated in other settings, and ultimately, in a randomized controlled trial.

PTEN Protein Loss by Immunostaining: Analytic Validation and Prognostic Indicator for a High Risk Surgical Cohort of Prostate Cancer Patients

Purpose: Analytically validated assays to interrogate biomarker status in clinical samples are crucial for personalized medicine. PTEN is a tumor suppressor commonly inactivated in prostate cancer that has been mechanistically linked to disease aggressiveness. Though deletion of PTEN, as detected by cumbersome FISH spot counting assays, is associated with poor prognosis, few studies have validated immunohistochemistry (IHC) assays to determine whether loss of PTEN protein is associated with unfavorable disease. Experimental Design: PTEN IHC was validated by employing formalin fixed and paraffin-embedded isogenic human cell lines containing or lacking intact PTEN alleles. PTEN IHC was 100% sensitive and 97.8% specific for detecting genomic alterations in 58 additional cell lines. PTEN protein loss was then assessed on 376 prostate tumor samples, and PTEN FISH or high resolution single nucleotide polymorphism microarray analysis was done on a subset of these cases. Results: PTEN protein loss, as assessed as a dichotomous IHC variable, was highly reproducible, correlated strongly with adverse pathologic features (e.g., Gleason score and pathologic stage), detected between 75% and 86% of cases with PTEN genomic loss, and was found at times in the absence of apparent genomic loss. In a cohort of 217 high risk surgically treated patients, PTEN protein loss was associated with decreased time to metastasis. Conclusion: These studies validate a simple method to interrogate PTEN status in clinical specimens and support the utility of this test in future multicenter studies, clinical trials, and ultimately perhaps for routine clinical care. Clin Cancer Res; 17(20); 6563–73. ©2011 AACR.

Death in Patients With Recurrent Prostate Cancer After Radical Prostatectomy: Prostate-Specific Antigen Doubling Time Subgroups and Their Associated Contributions to All-Cause Mortality

PURPOSE Among patients with biochemical recurrence after radical prostatectomy, we found previously that postoperative prostate-specific antigen doubling time (PSADT) was associated with risk of prostate cancer death. However, given the small number of patients in the highest risk PSADT subgroup, it is unclear which PSADT subgroups contribute the greatest to prostate cancer-specific death and how this influences all-cause mortality. PATIENTS AND METHODS This study was a retrospective analysis of 379 patients treated with radical prostatectomy between 1982 and 2000 who had a biochemical recurrence and PSADT data available. Mean and median follow-up after surgery was 11.4 (standard deviation, 5.4) and 11.0 years, respectively (range, 1.6 to 23.0 years). RESULTS Shorter PSADT was significantly associated with prostate cancer-specific and all-cause mortality (P < .001). Although patients with a PSADT less than 3 months were at the greatest risk of death, because of the limited number of patients in this group, they accounted for only 13% of prostate cancer deaths at 15 years after biochemical recurrence, whereas patients with an intermediate PSADT (3.0 to 8.9 months) accounted for 58% of all prostate cancer deaths. Among patients with a PSADT less than 15 months, prostate cancer accounted for 90% of all deaths. Only patients in the slowest PSADT subgroup (> or = 15 months) had a greater risk of competing-causes mortality compared with that from prostate cancer. CONCLUSION Among a select cohort of young, healthy patients with PSA recurrence after radical prostatectomy and a PSADT less than 15 months, prostate cancer accounted for an estimated 90% of all deaths by 15 years after recurrence. The majority of prostate cancer deaths occurred among patients with an intermediate PSADT (3.0 to 8.9 months).

Radical prostatectomy for clinical stage T3a disease.

Men with clinical stage T3a disease are at high risk and are often encouraged to undergo radiation therapy with concomitant hormonal therapy. The long‐term outcomes among men treated with radical prostatectomy for clinical stage T3a disease were examined.

The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up.

Study Type – Prognosis (cohort)

African American Men With Very Low–Risk Prostate Cancer Exhibit Adverse Oncologic Outcomes After Radical Prostatectomy: Should Active Surveillance Still Be an Option for Them?

PURPOSE Active surveillance (AS) is a treatment option for men with very low-risk prostate cancer (PCa); however, favorable outcomes achieved for men in AS are based on cohorts that under-represent African American (AA) men. To explore whether race-based health disparities exist among men with very low-risk PCa, we evaluated oncologic outcomes of AA men with very low-risk PCa who were candidates for AS but elected to undergo radical prostatectomy (RP). PATIENTS AND METHODS We studied 1,801 men (256 AA, 1,473 white men, and 72 others) who met National Comprehensive Cancer Network criteria for very low-risk PCa and underwent RP. Presenting characteristics, pathologic data, and cancer recurrence were compared among the groups. Multivariable modeling was performed to assess the association of race with upgrading and adverse pathologic features. RESULTS AA men with very low-risk PCa had more adverse pathologic features at RP and poorer oncologic outcomes. AA men were more likely to experience disease upgrading at prostatectomy (27.3% v 14.4%; P < .001), positive surgical margins (9.8% v 5.9%; P = .02), and higher Cancer of the Prostate Risk Assessment Post-Surgical scoring system (CAPRA-S) scores. On multivariable analysis, AA race was an independent predictor of adverse pathologic features (odds ratio, [OR], 3.23; P = .03) and pathologic upgrading (OR, 2.26; P = .03). CONCLUSION AA men with very low-risk PCa who meet criteria for AS but undergo immediate surgery experience significantly higher rates of upgrading and adverse pathology than do white men and men of other races. AA men with very low-risk PCa should be counseled about increased oncologic risk when deciding among their disease management options.

Clinical and Pathologic Outcome After Radical Prostatectomy for Prostate Cancer Patients With a Preoperative Gleason Sum of 8 to 10

Men with a biopsy Gleason sum of 8 to 10 are considered high‐risk. The current study sought to identify whether there was a subset of men with high biopsy Gleason sums who would have a good pathologic and biochemical outcome with surgical monotherapy. To increase the generalizability of the findings, data were used from patients treated at 2 very different practice settings: a tertiary care referral center (Johns Hopkins Hospital) and multiple equal‐access medical centers (Shared Equal Access Regional Cancer Hospital [SEARCH] Database).

Impact of surgical technique (open vs laparoscopic vs robotic-assisted) on pathological and biochemical outcomes following radical prostatectomy: an analysis using propensity score matching

Study Type – Therapy (case series)

Tissue-based Genomics Augments Post-prostatectomy Risk Stratification in a Natural History Cohort of Intermediate- and High-Risk Men.

BACKGROUND Radical prostatectomy (RP) is a primary treatment option for men with intermediate- and high-risk prostate cancer. Although many are effectively cured with local therapy alone, these men are by definition at higher risk of adverse pathologic features and clinical disease recurrence. It has been shown that the Decipher test predicts metastatic progression in cohorts that received adjuvant and salvage therapy following RP. OBJECTIVE To evaluate the Decipher genomic classifier in a natural history cohort of men at risk who received no additional treatment until the time of metastatic progression. DESIGN, SETTING, AND PARTICIPANTS Retrospective case-cohort design for 356 men who underwent RP between 1992 and 2010 at intermediate or high risk and received no additional treatment until the time of metastasis. Participants met the following criteria: (1) Cancer of the Prostate Risk Assessment postsurgical (CAPRA-S) score ≥3; (2) pathologic Gleason score ≥7; and (3) post-RP prostate-specific antigen nadir <0.2 ng/ml. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary endpoint was defined as regional or distant metastases. Time-dependent receiver operating characteristic (ROC) curves, extension of decision curve analysis to survival data, and univariable and multivariable Cox proportional-hazards models were used to measure the discrimination, net benefit, and prognostic potential of genomic and pathologic risk factors. Cumulative incidence curves were constructed using Fine-Gray competing-risks analysis with appropriate weighting of the controls to account for the case-cohort study design. RESULTS AND LIMITATIONS Ninety six patients had unavailable tumor blocks or failed microarray quality control. Decipher scores were then obtained for 260 patients, of whom 99 experienced metastasis. Decipher correlated with increased cumulative incidence of biochemical recurrence, metastasis, and prostate cancer-specific mortality (p<0.01). The cumulative incidence of metastasis was 12% and 47% for patients with low and high Decipher scores, respectively, at 10 yr after RP. Decipher was independently prognostic of metastasis in multivariable analysis (hazard ratio 1.26 per 10% increase; p<0.01). Decipher had a c-index of 0.76 and increased the c-index of Eggener and CAPRA-S risk models from 0.76 and 0.77 to 0.86 and 0.87, respectively, at 10 yr after RP. Although the cohort was large, the single-center retrospective design is an important limitation. CONCLUSIONS In a patient population that received no adjuvant or salvage therapy after prostatectomy until metastatic progression, higher Decipher scores correlated with clinical events, and inclusion of Decipher scores improved the prognostic performance of validated clinicopathologic risk models. These results confirm the utility already reported for Decipher. PATIENT SUMMARY The Decipher test improves identification of patients most at risk of metastatic progression and death from prostate cancer after radical prostatectomy.