Sanda, Martin G.

PURPOSE Radical prostatectomy (RP) alone is often inadequate in curing men with clinically localized, high-risk prostate cancer (PC). We hypothesized that chemohormonal therapy (CHT) with androgen-deprivation therapy plus docetaxel before RP would improve biochemical progression–free survival (BPFS) over RP alone. PATIENTS AND METHODS Men with clinically localized, high-risk PC were assigned to RP alone or neoadjuvant CHT with androgen deprivation plus docetaxel (75 mg/m 2 body surface area every 3 weeks for 6 cycles) and RP. The primary end point was 3-year BPFS. Biochemical failure was defined as a serum prostate-specific antigen level > 0.2 ng/mL that increased on 2 consecutive occasions that were at least 3 months apart. Secondary end points included 5-year BPFS, overall BPFS, local recurrence, metastasis-free survival (MFS), PC-specific mortality, and overall survival (OS). RESULTS In total, 788 men were randomly assigned. Median follow-up time was 6.1 years. The overall rates of grade 3 and 4 adverse events during chemotherapy were 26% and 19%, respectively. No difference was seen in 3-year BPFS between neoadjuvant CHT plus RP and RP alone (0.89 v 0.84, respectively; 95% CI for the difference, −0.01 to 0.11; P = .11). Neoadjuvant CHT was associated with improved overall BPFS (hazard ratio [HR], 0.69; 95% CI, 0.48 to 0.99), improved MFS (HR, 0.70; 95% CI, 0.51 to 0.95), and improved OS (HR, 0.61; 95% CI, 0.40 to 0.94) compared with RP alone. CONCLUSION The primary study end point, 3-year BPFS, was not met. Although some improvement was seen in secondary end points, any potential benefit must be weighed against toxicity. Our data do not support the routine use of neoadjuvant CHT and RP in patients with clinically localized, high-risk PC at this time.

Objectives To determine the prognostic potential of a 24‐gene signature, Sig24, for identifying patients with prostate cancer who are at risk of developing metastases or of prostate cancer‐specific mortality (PCSM) after radical prostatectomy (RP). Patients and Methods Sig24 scores were calculated from previously collected gene expression microarray data from the Cleveland Clinic and Mayo Clinic (I and II). The performance of Sig24 was determined using time‐dependent c‐index analysis, Cox proportional hazards regression and Kaplan–Meier survival analysis. Results Higher Sig24 scores were significantly associated with higher pathological Gleason scores in all three cohorts. Analysis of the Mayo Clinic II cohort, which included time‐to‐event information, indicated that patients with high Sig24 scores also had a higher risk of developing metastasis (hazard ratio [HR] 3.78, 95% confidence interval [CI]: 1.96–7.29; P < 0.001) or of PCSM (HR 6.54, 95% CI: 2.16–19.83; P < 0.001). Conclusions The findings of the present study show the applicability of Sig24 for the prognosis of metastasis or PCSM after RP. Future studies investigating the combination of Sig24 with available prognostic tests may provide new approaches to improve risk stratification for patients with prostate cancer.

Objective To examine the use of the Prostate Health Index ( PHI ) as a continuous variable in multivariable risk assessment for aggressive prostate cancer in a large multicentre US study. Materials and Methods The study population included 728 men, with prostate‐specific antigen ( PSA ) levels of 2–10 ng/ mL and a negative digital rectal examination, enrolled in a prospective, multi‐site early detection trial. The primary endpoint was aggressive prostate cancer, defined as biopsy Gleason score ≥7. First, we evaluated whether the addition of PHI improves the performance of currently available risk calculators (the Prostate Cancer Prevention Trial [ PCPT ] and European Randomised Study of Screening for Prostate Cancer [ ERSPC ] risk calculators). We also designed and internally validated a new PHI ‐based multivariable predictive model, and created a nomogram. Results Of 728 men undergoing biopsy, 118 (16.2%) had aggressive prostate cancer. The PHI predicted the risk of aggressive prostate cancer across the spectrum of values. Adding PHI significantly improved the predictive accuracy of the PCPT and ERSPC risk calculators for aggressive disease. A new model was created using age, previous biopsy, prostate volume, PSA and PHI , with an area under the curve of 0.746. The bootstrap‐corrected model showed good calibration with observed risk for aggressive prostate cancer and had net benefit on decision‐curve analysis. Conclusion Using PHI as part of multivariable risk assessment leads to a significant improvement in the detection of aggressive prostate cancer, potentially reducing harms from unnecessary prostate biopsy and overdiagnosis.