Carolyn Evan

The risk of renal impairment in hormone-refractory prostate cancer patients with bone metastases treated with zoledronic acid†

Bisphosphonates have been used to treat bone metastases in hormone‐refractory prostate cancer (HRPC), but certain agents have been associated with renal toxicity. For this observational study, the authors assessed the risk of renal impairment in patients with HRPC who received zoledronic acid from December 1999 to April 2005.

Patients with Biopsy Gleason 9 and 10 Prostate Cancer Have Significantly Worse Outcomes Compared to Patients with Gleason 8 Disease

PURPOSE We examined differences in outcome in patients with biopsy Gleason score 8 vs 9-10 who received definitive local therapy. MATERIALS AND METHODS Using an institutional database we identified a cohort of 847 patients with biopsy Gleason 8-10 disease who received definitive local therapy with radiation therapy or radical prostatectomy between January 2001 and December 2011. Multivariable Cox modeling was used to assess the association of Gleason score 8 vs 9-10 with time to biochemical recurrence, metastasis and overall survival, and evaluate treatment by Gleason score interaction. Median followup in the cohort was 5.3 years. RESULTS Baseline patient characteristics were similar for biopsy Gleason 8 vs 9-10. Gleason 9-10 disease was associated with higher prostate specific antigen at diagnosis. As local treatment such patients were also more likely to have received radiation therapy (58% vs 46%, p = 0.001) and neoadjuvant/adjuvant androgen deprivation therapy (64% vs 49%, p <0.001). Those with higher grade disease were at increased risk for metastasis (HR 1.41, 95% CI 1.11-1.79). There was a trend toward an increased risk of death in Gleason 9-10 vs 8 cases (HR 1.28, 95% CI 0.98-1.66). The increased risk of death for Gleason 9-10 was mainly observed in patients treated with radical prostatectomy with or without additional radiation therapy (HR 1.74, 95% CI 1.15-2.65). CONCLUSIONS Patients with localized biopsy Gleason 9-10 disease treated with definitive local therapy had worse outcomes than those diagnosed with biopsy Gleason 8 disease. Clinical trials are urgently needed that incorporate newer approaches to Gleason 9-10 cancer.

Elevated IL-8, TNF-α, and MCP-1 in men with metastatic prostate cancer starting androgen-deprivation therapy (ADT) are associated with shorter time to castration-resistance and overall survival.

Chemokines and cytokines have been implicated in progression to castration‐resistant prostate cancer (CRPC).

Elevated insulin-like growth factor binding protein-1 (IGFBP-1) in men with metastatic prostate cancer starting androgen deprivation therapy (ADT) is associated with shorter time to castration resistance and overall survival.

Insulin‐like growth factor (IGF) and adipokines have been implicated in prostate cancer carcinogenesis.

Role of Androgen Deprivation Therapy in Early Salvage Radiation Among Patients With Prostate-Specific Antigen Level of 0.5 or Less

BACKGROUND The Radiation Therapy Oncology Group 96-01 randomized trial demonstrated the benefit of adding androgen deprivation therapy (ADT) to salvage radiotherapy for an increasing prostate-specific antigen (PSA) after prostatectomy, but it is unknown whether modern patients followed with ultrasensitive PSA and salvaged at a low PSA (ie, ≤ 0.5) also benefit from ADT. PATIENTS AND METHODS The cohort comprised 108 patients who received radical prostatectomy (RP), were followed by ultrasensitive PSA, and received salvage radiotherapy at a PSA of 0.5 or less. Sixty patients had negative margins, and 48 patients had positive margins at RP. Cox multivariable regression analysis was performed to identify factors associated with time to secondary PSA failure and included PSA at salvage, year of treatment, Gleason score, ADT use, margin status, T stage, and PSA doubling time. Occurrence of distant metastases was documented. RESULTS Median follow-up after radiation was 63.09 months. A total of 24 patients had a distant metastasis. In all patients, ADT use was associated with a decreased risk of recurrence (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.25-0.79; P = .006). On subgroup analysis, ADT was associated with a decreased risk of failure among patients with negative margins (HR, 0.27; 95% CI, 0.12-0.61; P = .002), but not among men with positive margins (HR, 0.78; 95% CI, 0.29-2.10; P = .63). CONCLUSIONS Even patients followed with ultrasensitive PSA and salvaged early with a PSA ≤ 0.5 seem to benefit from the addition of ADT to salvage radiation. However, this benefit seemed to be limited to men with negative margins; thus, men with positive margins and PSA ≤ 0.5 may be good candidates for salvage radiation alone.

Characterization of patients who present with de novo metastatic prostate cancer: Single-institution database analysis.

33 Background: Less than 5% of men in a PSA screened population present with denovo metastatic prostate cancer. We sought to characterize the clinical characteristics and survival of this unique group of men. METHODS Retrospective analysis of an institutional data-base - Dana Farber Cancer Institute - Prostate Clinical Research Information Systems (CRIS). All men with metastatic disease as their first presentation of prostate cancer were identified. Patient and disease characteristics were summarized descriptively. The distributions of the study endpoints were estimated using the Kaplan-Meier method with median and 95%CI reported. RESULTS The analytic cohort has 185 patients with a median follow-up of 7.8 years (95% CI:7.5,11.1) and 94% diagnosed after 1998. Median age at diagnosis is 62 years (Range: 42-86); PSA at diagnosis: Median (Q1-Q3) - 100.2 (23.0, 346.0). Metastases: 97% bone, 2% liver, 2% lung, 8% lymph node. The median time from metastasis diagnosis to start of androgen deprivation therapy (ADT) was 26 days, 139 of those who started ADT had subsequently started treatment for castration resistant prostate cancer (CRPC) - 2nd line hormonal therapy and/or chemotherapy. The median time from ADT to subsequent therapy for CRPC is 14 months with 95% (CI:12,16). 128 patients have died and the median overall survival is 48 months (95% CI:40, 51). CONCLUSIONS This unique cohort of patients at a referral institution tend to be younger and have an overall survival comparable to outcomes in modern day randomized hormone sensitive prostate cancer studies. Assessment of similar group in a multivariate analysis of a prospective trial is needed to confirm this observation. If confirmed, the data would suggest the responsiveness to therapy drives outcome rather than development of metastasis with or without a previously treated primary.

Clinical Outcomes of First-line Abiraterone Acetate or Enzalutamide for Metastatic Castration-resistant Prostate Cancer After Androgen Deprivation Therapy + Docetaxel or ADT Alone for Metastatic Hormone-sensitive Prostate Cancer

Background The CHAARTED (ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trials showed that the addition of docetaxel (D) to androgen deprivation therapy (ADT) prolonged longevity of men with metastatic hormone‐sensitive prostate cancer (mHSPC). However, the impact of upfront D on subsequent therapies is still unexplored. As abiraterone acetate (AA) and enzalutamide (E) are the most commonly used first‐line treatment for metastatic castration‐resistant prostate cancer (mCRPC), we aimed to assess whether they maintained their efficacy after ADT+D versus ADT alone. Patients and Methods A cohort of patients with mCRPC treated between 2014 and 2017 with first‐line AA or E for mCRPC was identified from 3 hospitals’ institutional review board‐approved databases. Patients were classified by use of D for mHSPC. This time frame was chosen as ADT+D became a valid therapeutic option for mHSPC in 2014, and it inherently entailed a short follow‐up time on AA/E. The endpoints included overall survival from ADT start, overall survival from AA/E start, and time to AA/E start from ADT start. Differences between groups were assessed using the log‐rank test. Results Of the 102 patients with mCRPC identified, 50 (49%) had previously received ADT alone, while 52 (51%) had ADT+D. No statistically significant difference in any of the evaluated outcomes was observed between the 2 cohorts. Yet, deaths in the ADT+D group were 12 versus 21 in the ADT alone, after a median follow‐up of 24.4 and 29.8 months, respectively. Conclusion In a cohort of ADT/ADT+D‐treated patients with mCRPC with short times to first‐line AA/E and follow‐up, the efficacy of AA/E is similar regardless of previous use of D. Micro‐Abstract Although an androgen deprivation therapy plus docetaxel regimen was shown to extend the survival of some patients with metastatic hormone‐sensitive prostate cancer compared with androgen deprivation therapy alone, currently, there is no report in the literature investigating the impact of upfront docetaxel on subsequent first‐line abiraterone acetate or enzalutamide for metastatic castration‐resistant prostate cancer. This study showed that their activity is maintained regardless of previous use of docetaxel for metastatic hormone‐sensitive prostate cancer. These findings can aid treatment decision‐making.

Duration of androgen deprivation therapy for high-risk prostate cancer: Application of randomized trial data in a tertiary referral cancer center.

33 Background: We wished to evaluate the incidence and predictors of the use of long-term (2-3 years) vs. shorter-term androgen deprivation therapy (ADT) in radiation-treated men with high-risk prostate cancer. Methods: We identified 302 patients from the Dana-Farber Cancer Institute patient registry diagnosed with high-risk prostate cancer (T3a or PSA > 20 ng/mL or Gleason score 8-10) between 1993 and 2015. We assessed the intended duration of ADT and used multivariable Cox regression to evaluate predictors of receiving shorter-course ADT than recommended by guidelines (< 2 years). Results: The course of ADT intended by physicians increased following the 2009 publication of trials showing the superiority of 2-3 years versus 4-6 months of ADT, with 43.5% intending ≥ 2 years before vs. 61.4% after (p=0.014). Starting in 2010, 49.4% of patients actually received less than 2 years of ADT. The most common reasons for receipt of shorter-course ADT were intolerance of ADT side effects, patient comorbidity/age, ...

Use of elevated insulin-like growth factor binding protein-1 (IGFBP-1) to predict outcomes in men with metastatic prostate cancer treated with androgen-deprivation therapy (ADT).

191 Background: IGF-1 has been shown to promote cancer growth by activation of PI3 kinase and downregulation of AMPK. IGFBP-1 shuttles IGF-1 across blood vessel membranes. Elevated IGFBP-1 blood levels may be indicative of tissue IGF-1 levels and has been associated with prostate cancer risk. We hypothesized that IGF-1 and IGFBP-1 blood levels might effect ADT efficacy. METHODS A retrospective analysis of IGF-1 and IGFBP-1 was undertaken in men commencing ADT for metastatic prostate cancer. Blood was drawn within one month of initiating ADT and stored. Proteins were measured using multiplex electrochemiluminescence assays. A cohort of 122 patients was compiled from a prospective trial (50 patients) and chart review (72 patients). A multivariate analysis (MVA) using a COX model was performed to identify associations between blood levels of the markers and time to the development of castration resistant prostate cancer (CRPC) and overall survival (OS). The covariates analyzed were age at time of ADT, ECOG score, race, baseline PSA, and extent of disease. RESULTS At time of initiating ADT the cohort had a median age of 67 years, PSA of 27.4 and 82% had ECOG 0. 91% were Caucasian. 62% had extensive metastatic disease. Median OS was 42.2 months. The median (med) baseline levels for IGF-1 was 75.6 ng/ml and for IGFBP-1 was 1844 pg/ml. As detailed in the table, patients with IGFBP-1 levels above the median had significantly shorter time to development of CRPC and OS on MVA. There was no association between IGF-1 levels and time to CRPC development or OS. CONCLUSIONS Elevated levels of IGFBP-1 are associated with shorter duration of ADT efficacy in men with metastatic prostate cancer. This correlative data supports the ongoing SWOG trial assessing whether IGF signaling blockade improves ADT efficacy, as has been seen in preclinical models. [Table: see text].

Use of elevated baseline IL-8, CCL-2, and TNFα to predict for shorter overall survival (OS) in men with metastatic prostate cancer initiating androgen-deprivation therapy (ADT).

13 Background: Inflammation associated chemokines and cytokines have been shown in preclinical models to lead to the induction of castration resistance. We assessed whether higher blood cytokines and chemokines were associated with shorter time to CRPC and OS in patients initiating ADT for metastatic prostate cancer. METHODS A retrospective analysis of inflammatory markers including IL1β, IL-6, IL-8, TNFα and CCL-2 was undertaken in men initiating ADT for metastatic prostate cancer. Proteins were measured using multiplex electrochemiluminescence assays. The analytical cohort of 122 patients included a prospective trial (50 patients) and chart review (72 patients). A multivariate COX model was used to investigate the relationship between serum markers of inflammation and time to CRPC and OS. The covariates were age at time of ADT, ECOG score, race, baseline PSA, and extent of disease. RESULTS At time of initiating ADT, the median age of the cohort was 67 years, median PSA was 27.4, 82% had an ECOG PS of 0, 62% had extensive metastatic disease and 91% were Caucasian. Median OS was 42.2 months. The median (med) baseline levels for IL8 was 9.3pg/ml, TNFα was 2.4 pg/ml and CCL-2 was 507.5 pg/ml. As detailed below, patients with elevated IL-8, TNFα and CCL-2 had a significantly shorter OS and showed a non-significant shorter time to CRPC. CONCLUSIONS In men with metastatic prostate cancer starting ADT, higher serum inflammatory markers are associated with poorer OS. This correlative data suggests that anti-inflammatory strategies which improved ADT efficacy in preclinical models may be relevant to the clinical setting. [Table: see text].