David D. Yang

Clinical and Genomic Characterization of Low-Prostate-specific Antigen, High-grade Prostate Cancer

BACKGROUND The consequences of low prostate-specific antigen (PSA) in high-grade (Gleason 8-10) prostate cancer are unknown. OBJECTIVE To evaluate the clinical implications and genomic features of low-PSA, high-grade disease. DESIGN, SETTING, AND PARTICIPANTS This was a retrospective study of clinical data for 494 793 patients from the National Cancer Data Base and 136 113 patients from the Surveillance, Epidemiology, and End Results program with cT1-4N0M0 prostate cancer (median follow-up 48.9 and 25.0 mo, respectively), and genomic data for 4960 patients from the Decipher Genomic Resource Information Database. Data were collected for 2004-2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariable Fine-Gray and Cox regressions were used to analyze prostate cancer-specific mortality (PCSM) and all-cause mortality, respectively. RESULTS AND LIMITATIONS For Gleason 8-10 disease, using PSA 4.1-10.0ng/ml (n=38 719) as referent, the distribution of PCSM by PSA was U-shaped, with an adjusted hazard ratio (AHR) of 2.70 for PSA ≤2.5ng/ml (n=3862, p<0.001) versus 1.97, 1.36, and 2.56 for PSA of 2.6-4.0 (n=4199), 10.1-20.0 (n=17 372), and >20.0ng/ml (n=16 114), respectively. By contrast, the distribution of PCSM by PSA was linear for Gleason ≤7 (using PSA 4.1-10.0ng/ml as the referent, n=359 898), with an AHR of 0.41 (p=0.13) for PSA ≤2.5ng/ml (n=37 812) versus 1.38, 2.28, and 4.61 for PSA of 2.6-4.0 (n=54 152), 10.1-20.0 (n=63 319), and >20.0ng/ml (n=35 459), respectively (pinteraction<0.001). Gleason 8-10, PSA ≤2.5ng/ml disease had a significantly higher PCSM than standard high-risk/very high-risk disease with PSA >2.5ng/ml (AHR 2.15, p=0.002; 47-mo PCSM 14% vs 4.9%). Among Gleason 8-10 patients treated with radiotherapy, androgen deprivation therapy was associated with a survival benefit for PSA >2.5ng/ml (AHR 0.87; p<0.001) but not ≤2.5ng/ml (AHR 1.36; p=0.084; pinteraction=0.021). For Gleason 8-10 tumors, PSA ≤2.5ng/ml was associated with higher expression of neuroendocrine/small-cell markers compared to >2.5ng/ml (p=0.046), with no such relationship for Gleason ≤7 disease. CONCLUSIONS Low-PSA, high-grade prostate cancer has very high risk for PCSM, potentially responds poorly to androgen deprivation therapy, and is associated with neuroendocrine genomic features. PATIENT SUMMARY In this study, we found that low-prostate-specific antigen, high-grade prostate cancer has a very high risk for prostate cancer death, may not respond well to androgen deprivation therapy, and is associated with neuroendocrine genomic features. These findings suggest that current nomograms and treatment paradigms may need modification.

Androgen deprivation therapy and risk of rheumatoid arthritis in patients with localized prostate cancer

Background Androgens are generally immunosuppressive, and men with untreated hypogonadism are at increased risk for autoimmune conditions. To date, there has been no evidence linking androgen deprivation therapy (ADT) to autoimmune diseases, including rheumatoid arthritis (RA). We investigated the association between ADT and RA in patients with prostate cancer. Patients and methods We identified 105 303 men age 66 years or older who were diagnosed with stages I-III prostate cancer from 1992 through 2006 using the Surveillance, Epidemiology, and End Results-Medicare linked database, excluding patients with a history of RA. χ2 test was used to compare 5-year Kaplan-Meier rates of RA diagnoses. Competing risk Cox regression using inverse probability of treatment weighting was utilized to examine the association between pharmacologic ADT and diagnosis of RA. Results The 43% of patients (N = 44 785) who received ADT experienced a higher 5-year rate of RA diagnoses compared with men who did not (5.4% versus 4.4%, P < 0.001). Receipt of any ADT was associated with a 23% increased risk of being diagnosed with RA (hazard ratio 1.23, 95% confidence interval 1.09-1.40, P = 0.001). The risk of being diagnosed with RA increased with a longer duration of ADT, from 19% with 1-6 months and 29% with 7-12 months to 33% with ≥13 months (Ptrend < 0.001). Conclusions Consistent with the immunosuppressive properties of androgens, we demonstrated for the first time that ADT was associated with an elevated risk of being diagnosed with RA in this large cohort of elderly men with prostate cancer. The risk was higher with a longer duration of ADT. Linking ADT to an increased risk of being diagnosed with an autoimmune condition adds to mounting evidence of the adverse effects of ADT that should prompt physicians to thoughtfully weigh its risks and benefits.

Association between androgen deprivation therapy and anxiety among 78 000 patients with localized prostate cancer

To examine whether any androgen deprivation therapy use or longer duration is associated with an increased risk of anxiety in patients with prostate cancer.

Low rates of androgen deprivation therapy use with salvage radiation therapy in patients with prostate cancer after radical prostatectomy

OBJECTIVE The RTOG 9601 and GETUG-AFU 16 randomized controlled trials demonstrated that the addition of androgen deprivation therapy (ADT) to salvage radiation therapy (SRT) improves progression-free and, for RTOG 9601, overall survival. We examined national trends in the use of ADT with SRT. MATERIALS AND METHODS Of the 484,009 patients in the National Cancer Database from 2004 to 2012 with localized or locally advanced prostate cancer treated with radical prostatectomy (RP), 4,200 men received SRT (≥6mo after surgery). We used Pearsons chi-squared test to evaluate changes in ADT use, and multiple logistic regression to examine predictors of ADT use. RESULTS Overall, 32.1% of SRT patients received ADT, which increased after initial results of RTOG 9601 showed an improvement in metastasis-free survival in 2010 (28.5% in 2008/2009 vs. 34.5% in 2011/2012, P = 0.006). Predictors of ADT use include presurgery prostate-specific antigen>20ng/ml vs.<10ng/ml (adjusted odds ratio [AOR] = 1.34, P = 0.002; 36.7% vs. 29.6%); positive vs. negative margins (AOR = 1.29, P = 0.001; 34.9% vs. 27.8%); Gleason 3+4 (AOR = 1.53; 21.3%), Gleason 4+3 (AOR = 2.40; 32.0%), or Gleason 8 to 10 (AOR = 4.49; 49.2%) vs. Gleason 2 to 6 (P≤0.005 for all; 13.2%); and pathologic T3a (AOR = 1.46; 30.9%), T3b (AOR = 2.50; 47.6%), or T4 (AOR = 4.14; 60.9%) vs. T2 (P<0.001 for all; 19.1%). Starting SRT 12 to 23.9 months (AOR = 0.69; 23.2%) or≥24 months (AOR = 0.25; 8.0%) after RP was associated with decreased odds of ADT use vs. starting SRT 6 to 8.9 months after RP (P≤0.002 for both; 35.0%). CONCLUSION Although less than one-third of SRT patients from the study era received ADT, there is evidence that physicians and patients have begun slowly adopting this practice with the 2010 reporting of a decrease in the cumulative incidence of metastases with the addition of ADT to SRT. Given the newly reported survival benefit of RTOG 9601, additional work will be necessary to identify which patients benefit the most from the use of ADT with SRT to individualize treatment.

Travel distance and stereotactic body radiotherapy for localized prostate cancer

Definitive stereotactic body radiotherapy (SBRT) represents an emerging and debated treatment option for patients with prostate cancer, with potential economic savings and reports of short‐term efficacy since 2006. The current study sought to define national trends in definitive prostate SBRT use and determine whether patterns vary by travel distance for treatment.

Pathologic Outcomes of Gleason 6 Favorable Intermediate-Risk Prostate Cancer Treated With Radical Prostatectomy: Implications for Active Surveillance

&NA; We examined the pathologic outcomes of 2807 men with Gleason 6 favorable intermediate‐risk (FIR) prostate cancer treated with radical prostatectomy; 25.5% of patients with prostate‐specific antigen of 10 to 20 ng/mL and 12.4% with cT2b to T2c stage harbored higher grade or stage disease, suggesting that Gleason 6 FIR patients with cT2b to T2c tumors might generally be reasonable candidates for active surveillance. Background: The safety of active surveillance (AS) for Gleason 6 favorable intermediate‐risk (FIR) prostate cancer is unknown. To provide guidance, we examined the incidence and predictors of upgrading or upstaging for Gleason 6 FIR patients treated with radical prostatectomy. Patients and Methods: We identified 2807 men in the National Cancer Database diagnosed from 2010 to 2012 with Gleason 6 FIR disease (<50% positive biopsy cores [PBC] with either prostate‐specific antigen [PSA] of 10‐20 ng/mL or cT2b‐T2c disease) treated with radical prostatectomy. Logistic regression was used to identify predictors of upgrading (Gleason 3+4 with tertiary Gleason 5 or Gleason ≥4+3) or upstaging (pT3‐4/N1). Results: Fifty‐seven percent of the cohort had PSA of 10 to 20 ng/mL; 25.5% patients with PSA of 10 to 20 ng/mL and 12.4% with cT2b to T2c disease were upgraded or upstaged. In multivariable analysis, predictors of upgrading or upstaging included increasing age (P = .026), PSA (P = .001), and percent PBC (P < .001), and black race versus white (P = .035) for patients with PSA of 10 to 20 ng/mL and increasing PSA (P = .001) and percent PBC (P < .001) for patients with cT2b to T2c disease. Men with PSA of 15.0 to 20.0 ng/mL or 37.5% to 49.9% PBC with PSA of 10 to 20 ng/mL had >30% risk of upgrading or upstaging, whereas cT2b to T2c patients with <12.5% PBC or PSA <5.0 ng/mL had <10% risk. Conclusion: We found that Gleason 6 FIR patients with cT2b to T2c tumors had a low risk of harboring higher grade or stage disease and would be reasonable AS candidates, whereas patients with PSA of 10 to 20 ng/mL had a high risk and might generally be poor AS candidates.

Receipt of definitive therapy in elderly patients with unfavorable-risk prostate cancer

Conservative management of aggressive prostate cancer in the elderly without definitive therapy has been associated with a 10‐year prostate cancer‐specific mortality of approximately 50%. The authors examined the prevalence of definitive therapy in elderly patients with intermediate‐risk or high‐risk disease.

Androgen Deprivation Therapy and Overall Survival for Gleason 8 Versus Gleason 9–10 Prostate Cancer

BACKGROUND While the addition of androgen deprivation therapy (ADT) to external beam radiation therapy (EBRT) is known to improve overall survival (OS) in Gleason 8-10 (Grade Group 4-5) prostate cancer (PCa), it has been hypothesized that Gleason 9-10 disease, which is less differentiated than Gleason 8 disease, may be less sensitive to ADT. OBJECTIVE To examine the association between ADT and OS for Gleason 8 versus Gleason 9-10 PCa. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study of 20 139 men from the National Cancer Database with localized or locally advanced, Gleason 8-10 PCa who received EBRT. Data were collected from 2004 to 2012. INTERVENTION ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cox proportional hazards regression was used to examine the association between ADT and OS. RESULTS AND LIMITATIONS Overall, 9509 (78%) of the 12 160 men with Gleason 8 disease and 6908 (87%) of the 7979 men with Gleason 9-10 disease received ADT. On multivariable analysis, ADT was associated with a significant improvement in OS for Gleason 8 patients (adjusted hazard ratio 0.78, 95% confidence interval 0.70-0.87, p<0.001) but not for Gleason 9-10 patients (adjusted hazard ratio 0.96, 95% confidence interval 0.84-1.11, p=0.6), with a significant interaction (pinteraction=0.020). A higher Gleason score (8, 9, 10) correlated with an increased adjusted hazard ratio for the association between ADT and OS (pinteraction=0.042). Our study may be limited by the relatively short follow-up (median of 4.0 yr). CONCLUSIONS In contrast to the significant survival advantage of ADT for Gleason 8 disease, our results suggest that Gleason 9-10 disease derives less survival benefit from ADT and that a higher Gleason score predicts lesser benefit. Consideration should be given to treatment intensification for Gleason 9-10 patients through enrollment in clinical trials or potentially adding novel antiandrogens or docetaxel, which have shown efficacy in both castration-resistant and castration-sensitive settings. PATIENT SUMMARY In this study, we examined the effect of androgen deprivation therapy (ADT) for Gleason 8 (Grade Group 4) versus Gleason 9-10 (Grade Group 5) prostate cancer. We found that Gleason 9-10 disease may derive a smaller survival benefit from ADT than Gleason 8 disease.

Optimizing androgen deprivation therapy with radiation therapy for aggressive localized and locally advanced prostate cancer

Radiation therapy with androgen deprivation therapy (ADT) has historically been one of the mainstays of treatment for intermediate- and high-risk prostate cancer. The benefit of ADT likely derives from both enhancing local control and inhibiting micrometastatic disease. While level 1 evidence has demonstrated the benefits of 4-6 months of ADT for all men with intermediate-risk disease, further stratification of intermediate-risk prostate cancer into favorable and unfavorable subgroups indicates that ADT may not be necessary for favorable intermediate-risk disease but likely still provides a survival advantage for unfavorable intermediate-risk disease, even in the dose escalation era. Long-course ADT, consisting of 2-3 years of treatment, is the standard of care for high-risk prostate cancer managed with RT based on phase III trials. However, emerging data from a randomized trial raises the possibility that 18 months of ADT could be sufficient for select high-risk patients. The desire to minimize exposure to ADT lies in its many adverse effects, including the potential for cardiovascular harm in certain patients with significant coexisting comorbidity, possibly increased risk for neurocognitive and psychiatric events, and the well-documented metabolic changes. Providers need to carefully weigh these potential risks with the known survival benefits of ADT in aggressive localized and locally advanced prostate cancer.

Brachytherapy monotherapy may be sufficient for a subset of patients with unfavorable intermediate risk prostate cancer

PURPOSE/OBJECTIVE(S) Brachytherapy (BT) monotherapy is a well-established treatment modality for favorable intermediate risk (FIR) prostate cancer. However, patients with unfavorable intermediate risk (UIR) disease are often recommended trimodality therapy involving BT, androgen deprivation therapy (ADT), and external beam radiation therapy (EBRT). We sought to investigate the relative benefit of supplemental therapies (ADT and/or EBRT) for FIR and UIR prostate cancer in a large dataset. MATERIALS/METHODS We identified 3,723 patients with intermediate risk prostate cancer treated with BT between 1997 and 2013, including 1,989 and 1,734 patients with FIR and UIR disease, respectively. For the FIR cohort, Fine and Grays competing risks regression model was used to evaluate whether there was a difference in prostate cancer specific mortality (PCSM) between BT vs. BT + supplemental therapy (ADT, EBRT, or both). For the UIR cohort, this regression model was used to evaluate whether supplemental ADT, EBRT, or both decreased PCSM beyond BT alone. Both regression models were adjusted for clinical and treatment-related factors. RESULTS The median follow-up periods were 7.7 years (interquartile range: 5.4-10.5) for the FIR cohort and 7.8 years (interquartile range: 5.3-10.6) for the UIR cohort. For the FIR cohort, there was no difference in PCSM between BT monotherapy vs. BT + supplemental therapy (adjusted hazard ratio [AHR] = 1.70; 95% CI: 0.46-6.29; P = 0.43). For the UIR cohort, supplemental EBRT (AHR = 2.66; 95% CI: 1.12-6.34; P = 0.03), ADT (AHR = 0.96; 95% CI: 0.38-2.43; P = 0.93), or both (AHR = 1.46; 95% CI: 0.42-5.01; P = 0.55) were not associated with improved PCSM compared with BT alone. CONCLUSION In our analysis, supplemental therapies did not offer an improvement in PCSM compared with BT alone for FIR or UIR prostate cancers. Further prospective clinical trials are required to determine whether BT monotherapy may be sufficient for a subset of patients with UIR disease.