bluuebunny/crossref_metadata_2025 huggingface dataset:
Disparities in prostate cancer treatment associated with population density of the county of residence.
Authors: Cary Clint , Odisho Anobel , Cooperberg Matthew R.
Published: February 2017

117

Background: We sought to assess disparities in primary treatment of prostate cancer by examining the effect of population density of the county of residence on treatment for clinically localized prostate cancer and quantify variation in primary treatment attributable to county and SEER site. Methods: Participants included 138,226 men with clinically localized prostate cancer who underwent surgery, radiation, or conservative therapy in the Surveillance, Epidemiology, and End Result (SEER) database diagnosed in 2005 through 2008. Mixed effects hierarchical logit models were used to examine the effect of population density of the county of residence on treatment while accounting for the random effects of counties nested within SEER sites. In order to quantify the effect of county and SEER site on individual treatment, the percent of total variance in treatment attributable to county of residence and SEER site was estimated with residual intraclass correlation coefficients. Results: Men in metropolitan counties had 23% higher odds of being treated compared with men in rural counties, controlling for number of urologists per county as well as patient clinical and sociodemographic characteristics. Age, race/ethnicity, PSA at diagnosis, and tumor characteristics were also significant predictors of treatment in the multivariable model. The percent of variation in treatment attributable to the county of residence was consistently higher than that attributable to SEER site. 3% (95% CI: 1.2%-6.2%) of the total variation in treatment was attributable to SEER site, while 6% (95% CI: 4.3%-9.0%) of variation was attributable to county of residence, controlling for clinical and sociodemographic characteristics. This variation at the county and SEER site increased to 4% and 10%, respectively, when specific type of treatment (surgery or radiation) was assessed. Conclusions: Variation in treatment for localized prostate cancer exists for men living in different population dense counties of the country. These findings highlight the need for comparative effectiveness research and health policy initiatives to advance prostate cancer research and reduce disparities in current clinical practice.
Influence of ischemia on tissue androgens in eugonadal and androgen-deprived men treated with prostatectomy.
Authors: Montgomery Robert B. , Risk Michael Christopher , Lin Daniel W. , Matsumoto Alvin M. , Marck Brett , Wright Jonathan L. , Nelson Peter , Mostaghel Elahe A.
Published: February 2017

118

Background: Optimizing tissue androgen suppression may provide a higher rate of complete pathologic response in patients with localized prostate cancer (PCa). The ability to accurately assess tissue androgens may be influenced by ischemic time and catabolism after devascularization. This study was performed to determine if ischemia influences tissue androgen in eugonadal men and in men treated with various types of neoadjuvant androgen deprivation (ADT). Methods: Eugonadal men (n=12) or men treated with neoadjuvant ADT using LHRH agonist and Casodex or LHRH agonist with Dutasteride, Casodex or all three with Ketoconazole (n=34) underwent prostatectomy for localized PCa. Tissue was acquired by needle biopsy at the time of ligation of the vascular pedicles, at prostate removal and at 30 minutes after prostate removal. Prostate tissue was flash-frozen and tissue dihydrotestosterone (DHT) and testosterone (T) were determined by LC/MS/MS. Change in tissue androgens from clamp was assessed at each time point. Trends in androgen levels were assessed by ANOVA for eugonadal men and within each treatment group Results: Average time from clamp to removal was 23 minutes (± 8) and from removal to subsequent biopsy 32 minutes (± 2). There was no evidence for a significant change in T or DHT over the time intervals tested (one way ANOVA p>0.05 for all measures) except in patients treated with LHRH agonist and Casodex alone. In this group of patients, T declined by 34%by the time of prostate removal, and by 83% at 30 minutes after removal when compared to levels at clamp (one way ANOVA p=0.017, test for linear trend =0.007). In all other treatment groups, both T and DHT were stable for 60 minutes. Conclusions: Assessment of DHT levels in prostate tissue at prostatectomy is not compromised by ischemia. Tissue sampling from 30-60 minutes after vascular clamping yields a stable measure of tissue DHT in the majority of patients. In the absence of SRD5A blockade, testosterone sampling in castrate men is sensitive to ischemia, and delayed sampling underestimates tissue androgen levels due to ischemia-related metabolism. These results lend important insight into clinical trial design and translational endpoints.
Retrospective registry evaluating the PSA flare phenomenon with cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Angelergues Antoine , Mercier Florence , Flechon Aude , Guillot Aline , Le Moulec Sylvestre , Gravis Gwenaelle , Beuzeboc Philippe , Massard Christophe , Fizazi Karim , De La Motte Rouge Thibault , Elaidi Reza-Thierry , Oudard Stephane
Published: February 2017

122

Background: PSA initial flare followed by a decrease is documented in up to 18% of mCRPC patients (pts) treated with docetaxel (D). There is no standard definition of this phenomenon, and its significance in terms of treatment efficacy and prognosis remains unclear. We evaluated the PSA flare incidence and characteristics with cabazitaxel (C), a new taxane developed to overcome D resistance, and its impact on outcome. Methods: A retrospective review of 84 consecutive pts (median 67 yrs) treated with C for mCRPC progressing during or after D was conducted in 8 French centers. Baseline characteristics, disease history, PSA values before and during C, overall survival (OS) and radiological or clinical progression-free survival (PFS) were collected. Results: At C initiation, most pts (84%) were ECOG 0-1, 59.5% had pain and 23.8% received ≥2 chemotherapy lines. Metastases were located in bone (92.9%), lymph nodes (48.8%) and visceral/soft tissues (9.5%). Median number of C cycles was 6 (range 2-14). Median OS and PFS from first C cycle were 16.4 and 6.7 months, respectively. Flare incidence, PFS and OS varied with the definition used (table). Definition [3] seems to us the most clinically relevant, and showed a close estimate of PFS compared to pts with immediate PSA decrease from baseline. We recommend to use this definition in clinical practice. Conclusions: PSA flare occurred in 16% pts treated with C and was associated with as good outcome as immediate responders. C should not be withdrawn prematurely in case of isolated initial PSA rise. This finding supports the PCWG 2 recommendation that early rise (prior to 12 weeks) with cytotoxics should be ignored in determining PSA response. [Table: see text]
From trial to practice: The Princess Margaret Hospital (PMH) experience with docetaxel and prednisone for men with metastatic castration resistant prostate cancer (mCRPC).
Authors: Templeton Arnoud , Wang Lisa , Vera-Badillo Francisco , Attalla Mirna , De Gouveia Paulo , Leibowitz-Amit Raya , Knox Jennifer J. , Moore Malcolm J. , Sridhar Srikala S. , Joshua Anthony Michael , Tannock Ian
Published: February 2017

125

Background: Docetaxel (75mg/m2every 3 weeks [q3w]) plus prednisone (5mg bid) is standard first-line chemotherapy for men with mCRPC since FDA approval in 2004. It is unclear how results from trials translate to daily practice. Our hypothesis was that patients (pts) treated in trials would have better outcome and less toxicity. Methods: We reviewed all pts with mCRPC treated with docetaxel at PMH until the end of 2011. Primary outcomes were overall survival (OS) and PSA response rate (confirmed decline ≥ 50%). Secondary outcomes were reasons for discontinuation, febrile neutropenia and predictive factors for the primary outcomes. Data were analyzed using the Kaplan-Meier method and Cox regression for OS. Results: 438 men were treated between 2001 and 2011. At start of treatment median age was 71 (range 44 – 90) years, 80 (18%) had visceral metastasis, and the median number of docetaxel cycles was 6 (range 1 – 15). Outcomes are shown in the table. Reasons for treatment discontinuation were progressive disease (38%), completion of treatment (27%), toxicity (22%), death within 30 days of last administration (5%), and other reasons (8%). In multivariate analysis better performance status (p < 0.0001), and more recent treatment (p < 0.0001) were baseline factors associated with longer OS for pts receiving primary treatment with docetaxel q3w. Conclusions: In less selected pts with CRPC treated with docetaxel/prednisone PSA response rates are similar, OS shorter and toxicity more frequent as compared to men treated in the pivotal or in other trials. Supported by a research grant from CIHR. [Table: see text]
Feasibility of continuing docetaxel-based therapy in patients with metastatic castrate-resistant prostate cancer (mCRPC) that experience hypersensitivity reactions (HSR).
Authors: Couvillon Anna , Beatson Melony A. , Harold Nancy , Karzai Fatima H. , Madan Ravi Amrit , Gulley James L. , Dahut William L.
Published: February 2017

132

Background: Patients that receive docetaxel are observed closely for HSRs. Severe HSRs have been reported in patients premedicated with corticosteroids. The rate of allergic reactions reported in the TAX 327 trial (n=332) was 8% (any grade) and 1% (grade 3/4). In TAX 327 treatment was stopped after a total of 10 cycles of docetaxel. A recent trial conducted at the NCI has included patients treated with docetaxel-based therapy until radiographic progression with no cap on total dose or cycle number. Most patients have had significantly more than 10 cycles (median greater than 16 with a range of 1 to 48; however, some cycles did not include docetaxel). Given the increased incidence of HSR to docetaxel on our protocols, we developed guidelines for the clinical management of HSRs to docetaxel. Methods: We reviewed the literature on taxane HSRs and developed a 4-step clinical management guideline for the prevention and treatment of HSRs to docetaxel. Our guidelines utilize increasing amounts of H1/H2 antihistamines, corticosteroids, slower infusion rates of docetaxel, and/or decreasing concentrations of docetaxel. Results: From August 2009 to present, 63 mCRPC patients have been treated with docetaxel-based therapy. Twenty-three patients (37%) have experienced a HSR to docetaxel. HSRs initially occurred at cycle 1 (17%), cycle 2 (48%), cycle 3 (17%), cycle 4 (n=2), cycle 14 (n=1), cycle 16 (n=1). All patients were re-challenged with docetaxel using our 4-step clinical management guideline approach. Ten patients continued docetaxel without further HSRs. The remaining 13 patients continued to experience HSRs but were able to safely complete each infusion of docetaxel. No patients required discontinuation of therapy. Of the 23 patients with HSRs, 21 received more than 10 cycles of therapy with a median of 17 and a range of 1 to 38. Conclusions: Patients with mCRPC disease that is taxane sensitive and who experience HSR to docetaxel can continue to receive docetaxel safely. Most of these patients demonstrated a continued PSA, clinical, and radiographic response to therapy.
Induction of endothelial proliferation and angiogenesis through activating the ERK1/2/EGF pathway mediate by CXC chemokine receptor 2 by chemokine (C-X-C motif) ligand 1.
Authors: Miyake Makito , Goodison Steve , Gomes Evan , Rizwani Wasia , Ross Shanti , Zhang Ge , Rosser Charles Joel
Published: February 2017

138

Background: Endothelial cell growth and proliferation are critical for tumoral angiogenesis. We report here that blockade of Chemokine (C-X-C motif) ligand 1 (CXCL1) results in reduction of human endothelial cell proliferation and its ability to induce angiogenesis. Methods: Two human endothelial cell lines, HUVEC and HDMEC, were used in the in vitro assays. Proliferation assay and matrigel tube formation assay were performed to test the inhibitory effect of anti-CXCL antibody on the activity of endothelial cells in vitro. Matrigel plug assay in nude mice was performed to test the in vivo angiogenic activity of CXCL1. Results: CXCL1 interacts with its receptor CXC chemokine Receptor 2 and induces endothelial cell proliferation, whereas blockade of CXCL1 is associated with reduction in cellular proliferation through a decrease in levels of cyclin D and cdk4 and inhibition of angiogenesis through EGF and ERK 1/2. Targeting CXCL1 inhibits neoangiogenesis but has no effect on disrupting established vasculature. Furthermore targeting CXCL1 is associated with reduction in migration of human endothelial cells in an in vitro model. Additionally, neutralizing antibody against CXCL1 in a xenograft angiogenesis model resulted in inhibition of angiogenesis. Conclusions: CXCL1-induced regulation of angiogenesis has not been studied extensively in human cancers, thus these findings illustrate a novel contribution of CXCL1 interactions in pathological angiogenesis. Therefore, the ability to selectively modulate CXCL1, specifically in tumoral angiogenesis, may promote the development of novel oncologic therapeutic strategies.
Response to cabazitaxel in CRPC patients previously treated with docetaxel and abiraterone acetate.
Authors: Pezaro Carmel Jo , Le Moulec Sylvestre , Albiges Laurence , Omlin Aurelius Gabriel , Loriot Yohann , Bianchini Diletta , Gross-Goupil Marine , Lorente David , de la Motte Rouge Thibault , Beuzeboc Philippe , Attard Gerhardt , Guillot Aline , Fizazi Karim , De Bono Johann Sebastian , Massard Christophe
Published: February 2017

155

Background: Cabazitaxel, which is a tubulin-binding chemotherapy, and the CYP-17 androgen biosynthesis inhibitor abiraterone acetate (AA) are both approved for patients with metastatic castration resistant prostate cancer (CRPC) following docetaxel chemotherapy. Recent preclinical data suggest that taxanes impact AR signalling and could imply cross-resistance between new AR targeting treatments and taxane chemotherapy. The aim of this study is to evaluate the antitumor activity of cabazitaxel after AA. Methods: We retrospectively evaluated antitumor activity of cabazitaxel in patients (pts) with metastatic CRPC and progressive disease after docetaxel and AA. Radiological response by RECIST, PSA response by PCWG2 criteria and symptomatic benefit were examined. Results: 89 pts were treated with third-line cabazitaxel, after docetaxel (median 8 cycles; range: 4-12), and AA (median duration of treatment 4.8 months, range: 1-55 months). At cabazitaxel initiation median age was 68 years (range: 53-83), ECOG performance status was 0 or 1 in 70% of pts, and median PSA was 309 ng/ml (range: 3.75-9150). Bone, lymph node and visceral metastases were present in 80 pts (89%), 37 pts (41%), and 12 pts (13%) respectively. An average of 6 cycles of cabazitaxel (range 1-15) were administered. All pts had PSA data available and 44 (49%; 95% CI 39-60%) had a 50% or greater PSA decline. In the 35 pts with RECIST evaluable disease, 7 (20%; 95% CI 8-37%) had a partial response. Conclusions: In men with metastatic CRPC cabazitaxel appears to retain activity in the third-line setting following docetaxel and AA.
Influence of concurrent medications on PSA doubling time (PSADT) in patients (pts) with nonmetastatic biochemically relapsed prostate cancer (BRPC M0) after local therapy (tx).
Authors: Keizman Daniel , Ish-Shalom Maya , Maimon Natalie , Gottfried Maya , Roubinov Keren , Pili Roberto , Sinibaldi Victoria J. , Hammers Hans J. , Carducci Michael Anthony , Eisenberger Mario A. , Mermershtain Wilmosh
Published: February 2017

160

Background: In patients with BRPC(M0) after local tx, the most important prognostic factor is probably the PSADT (high risk < 3, intermediate risk 3–8.9, low risk ≥9.0 months). Pre-clinical and clinical studies in several cancer types have shown that commonly prescribed medications may inhibit tumor growth. The effect of commonly prescribed medications on PSADT in pts with BRPC(M0) is poorly defined. We aimed to study the effect of commonly prescribed medications on PSADT in pts with BRPC (M0) after local tx. Methods: We reviewed the records of 156 BRPC(M0) pts enrolled in 1 prospective (Keizman, CCR 2010) and two retrospective (Keizman, prostate 2012; Mermershtain, EMUC 2011) studies, in 2 centers across 2 countries. The effect of clinicopathologic factors and the use of statins, aspirin, and angiotensin system inhibitors (ASIs; ACE-I and ARBs) on initial PSADT (from the time of first PSA relapse to the initiation of any systemic tx) was analyzed using the Mann-Whitney or Kruskal-Wallis tests and regression analyses. Results: In the whole patient cohort (n=156), median age was 62, prior local tx consisted of radical prostatectomy in128 pts and EBRT in 28, and median PSADT was 6.7 months (mos). Median PSADT in ASIs users (n=48) vs non users (n=108) was 7.85 vs 5.6 mos (p=0.011). In multivariate analysis, the use of ASIs and Gleason score were associated with median PSADT. The use of statins (n=58) or aspirin (n=72), primary tx modality, and time from primary tx to PSA relapse had no significant effect on median PSADT. PSADT risk grouping in ASIs users vs non users was low 48% vs 27%, intermediate 42% vs 49%, and high 10% vs 24% (p=0.02). In multivariate analysis, the use of ASIs, Gleason score, and prior ADT were associated with PSADT risk grouping. The use of statins or aspirin, primary tx modality, and time from primary tx to PSA relapse had no significant effect on PSADT risk grouping. Conclusions: The use of ASIs, Gleason score, and prior ADT may be associated with PSADT (median and risk grouping) of pts with BRPC (M0) after local tx. This should be investigated prospectively, and if validated, applied in clinical practice and clinical trials.
Patient benefit from salvage radiation for prostate cancer.
Authors: Gebhardt Brian Joseph , McDonald Andrew M. , Bae Sejong , Singh Karan P. , Jacob Rojymon , Dobelbower Michael C. , Kim Robert Y. , Yang Eddy Shih-Hsin , Fiveash John B.
Published: February 2017

175

Background: To identify post-operative prostate cancer patients who are unlikely to achieve long-term biochemical control following salvage radiotherapy (SRT). We hypothesize that patients with node-positive disease, no nadir after radical prostatectomy (RP), or a high pre-radiotherapy (pre-RT) PSA levelwill have a low chance of benefitting from SRT. Methods: Ninety patients who received SRT following RP were retrospectively analyzed to determine factors associated with biochemical failure. Patients on continuous androgen deprivation therapy (ADT) were excluded from statistical analysis. Results: Median follow-up was 30 months (range 6-120). The overall projected 3-year bPFS was 70%. Factors significantly associated with biochemical failure on univariate analysis included Gleason score, positive seminal vesicle invasion, PSA doubling time of 6 months or less, and pre-RT PSA greater than 1.0 ng/mL. All patients with a pre-RT PSA greater than 3.0 ng/mL failed. Patients who did not reach an undetectable nadir following RP had 55% 3-year bPFS compared with 79% in those who did achieve an undetectable PSA (p=0.041). Multivariate analysis demonstrated that GS of 8 and pre-RT PSA were significant predictors. A separate analysis was performed on a subgroup of 8 patients with node-positive disease. Five patients failed at a median of 24 months (range 12-64). Of the remaining 3 patients, 2 had been maintained on long-term ADT, and 1 patient was 11 months out from treatment. Conclusions: Patients with node-positive disease are unlikely to achieve long-term biochemical control from SRT due to extra-prostatic disease spread. Although various factors may influence outcome, no other group demonstrated a very low chance of benefit. Patients with rising PSA benefit from early treatment before PSA rises above 1.0 ng/mL. [Table: see text]
Differential effects of galeterone, abiraterone, orteronel, and ketoconazole on CYP17 and steroidogenesis.
Authors: Jacoby Douglas Burtner , Williams Martin
Published: February 2017

184

Background: Because CYP17 has a central role in converting progestogens to androgens, inhibitors have been developed to treat CRPC. CYP17 has both hydroxylase and lyase catalytic functions. However, selective hydroxylase inhibition causes build-up of progestogens and mineralocorticoids, resulting in secondary mineralocorticoid excess (ME), edema, hypokalemia and hypertension (treated clinically with prednisone). We analyzed four inhibitors for their effects on CYP17 hydroxylase and lyase activities, and more globally on the steroidogenic pathway. Methods: Human CYP17 expressed in yeast microsomes was incubated with pregnenolone or 17α-hydroxypregnenolone and products quantitated using LC/MS/MS. Galeterone, abiraterone, orteronel or ketoconazole were added, and hydroxylase or lyase IC50 values calculated. In a separate experiment, H295R adenocarcinoma cells were incubated with a range of drug concentrations between 0.316 nM and 10 μM for 24 hours and media was analyzed for steroid production by LC/MS/MS. Results: All drugs inhibited CYP17. However, potency and selectivity for hydroxylase and lyase varied significantly. Galeterone was the most potent and selective CYP17 lyase inhibitor. Abiraterone most selectively inhibited hydroxylase, while orteronel and ketoconazole were less potent lyase inhibitors than galeterone. In the cell-based assay, all drugs inhibited testosterone synthesis ≥94% at 1 μM. However, at this concentration, evidence of hydroxylase inhibition was supported by significant elevation of progesterone (abiraterone increased 293-fold), mineralocorticoids (orteronel increased DOC 74-fold), or reductions in cortisol (abiraterone, orteronel, ketoconazole reduced by 91%, 70% and 94%, respectively). In contrast, galeterone produced minimal changes in cortisol (decreased 14%) and other intermediate precursors. Conclusions: Galeterone is a selective and potent CYP17 lyase inhibitor that also antagonizes and degrades the AR, and exhibits minimal evidence of deleterious steroid changes associated with ME. These experimental data recapitulate phase I clinical experience where no ME was observed or prednisone required in CRPC patients.
Prevalence of cardiovascular disease (CVD) risk factors and receipt of preventive care among prostate cancer (CaP) survivors in the United States.
Authors: Pearlstein Kevin Alexander , Hendrix Laura H. , Royce Trevor Joseph , Stokes William A. , Chen Ronald C.
Published: February 2017

185

Background: CVD is a major cause of mortality in CaP survivors. Prior claims-based studies have reported underutilization of preventive care in cancer survivors, but most CVD preventive care items are not available in claims data. We directly examined the prevalence of CVD risk factors and receipt of care in patients with these risk factors in two population-based data sources: National Health and Nutrition Examination Survey (NHANES) and National Health Interview Survey (NHIS) – both commonly used to examine patterns of care in the US. Methods: 2,938 (NHANES) and 452 (NHIS) men with CaP diagnosed from 1999 to 2011 were included. Statistical analysis accounted for sampling weight, and was stratifiedby Caucasian (CA) vs. non-CA. Results: CVD risk factors are highly prevalent (Table), and appear more so in non-Caucasian survivors. Further, 32% of survivors reported history of actual CVD (prior stroke, myocardial infarction, angina, or coronary heart disease). Overall, the majority of survivors receive preventive care. 89%of CA and non-CA survivors visited a primary care physician in the past 1 year. Among survivors with hypertension or hyperlipidemia, >80% received blood pressure or cholesterol checks within past 1 year. Rates of tobacco cessation and exercise were lower. Conclusions: CVD and associated risk factors are prevalent in CaP survivors. However, the majority of these survivors visit a primary care physician and receive CVD preventive care. [Table: see text]
Beyond IGRT: Daily real time planning (RTP)—Treatment of prostate cancer, clinical implementation, and technique.
Authors: Wong James Robert , Merrick Scott Andrew , Karim Mona , Goldberg Yana P. , Gao Jeff , Li Mei , Wilson Paula , Klingeman Madeline
Published: February 2017

191

Background: Image guided radiation therapy (IGRT) corrects for the interfractional movements of the target/CTV. However, the anatomic changes of CTV, and movements of the adjacent organs, are not accounted for. By modifying an online adaptive radiation technique proposed by Li, we have clinically deployed a daily “real-time treatment planning” (RTP) technique for treatment of primary prostate cancers. The technique, rationale and experience of our first 60 RTP treatments are presented. To our knowledge, this is the first clinical implementation of daily treatment planning. Methods: The RTP process is as follows: a) daily CT images are acquired via an in-room diagnostic CT-on-Rails; b) while IGRT evaluation is performed, new target and tissue contours (prostate, rectum and bladder) are drawn, c) new IMRT plan is computed (RTP plan); d) IGRT plan is compared to the RTP plan; e) if RTP plan is dosimetric superior, it will be delivered after f) necessary QA process. This entire process takes less than 20 minutes (excluding IMRT delivery). 60 RTP’s were delivered (10 daily RTP/patient) in 6 consecutive patients. Results: Auto-contouring via auto-segmentation was inadequate when compared to manual anatomic re-contouring. The RTP plan is always superior to or equal to the original IGRT plan. In 20% of the cases, the CTV-DVH by RTP improved by >10%. Slight changes in manual contouring variation can lead to significant change in volume variation. For example, with initial prostate volumes of 15, 20, 30, 40 and 50 cc, a 1 mm increase in contour variation results in an increase volume of 26%, 24%, 21%,19% and 17% respectively, and absolute volume increase of 3.9cc, 4.8cc, 6.2cc, 7.4cc and 8.6cc respectively. Rectal dose improved significantly with RTP when compared to IGRT. In one extreme case, the rectal dose improvement is shown (Table). Conclusions: Daily RTP is feasible for prostate cancer treatments and is superior to IGRT. RTP is especially necessary with extreme anatomic changes. [Table: see text]
Trends in use of intravenous bisphosphonates in patients with prostate cancer and newly diagnosed metastases to bone in two large U.S. integrated health systems.
Authors: Lamerato Lois , Glass Andrew , Richert-Boe Kathryn E. , Edelsberg John , Wolff Greg G. , Czapski Natalie , Dodge Tracy , Lopez Andrea , Chung Karen , Richhariya Akshara , Oster Gerry
Published: February 2017

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Background: Bone is a common site of metastatic involvement in patients (pts) with prostate cancer (PC). Bony metastases (mets) are associated with skeletal complications, which can cause significant morbidity and mortality. Intravenous bisphosphonates (IV BPs) have been proven to reduce the incidence and onset of skeletal complications. Patterns of use of IV BPs in clinical practice in pts with bone mets due to PC are largely unknown. Methods: Using the tumor registries and electronic data stores at two large US integrated health systems that serve a total of approximately 1.3 million persons, we retrospectively identified all pts aged ≥18 yrs with primary PC and newly diagnosed bone mets between 1/1/95 and 12/31/09. Information on all administrations of IV BPs between date of diagnosis of bone mets and death, loss to follow-up, or end of study was extracted from administrative data stores and electronic medical records, which also were reviewed by trained medical abstractors for evidence of skeletal-related events (SREs) (spinal cord compression, pathologic fracture, surgery to bone, radiation to bone). Results: We identified a total of 461 pts with primary PC and newly diagnosed bone mets. Mean (SD) age was 72.8 yrs (10.7 yrs); 75% were Caucasian, and 21% were African-American. Median duration of follow-up after diagnosis of bone mets was 1.3 yrs. One-fifth (20.2%) of study subjects received IV BPs (92% zoledronic acid, 8% pamidronate) during follow-up--10.8% prior to, and 9.3% after, first on-study SRE. Median time from diagnosis of bone mets to first administration of IV BPs was 1.7 yrs, and the median number of administrations was 3. The percentage of study subjects receiving IV BPs increased steadily over the 15-yr study period--from 7.5% among those newly diagnosed with bone mets in 1995-1999, to 19.8% among those newly diagnosed with bone mets in 2000-2004, to 27.5% among those newly diagnosed with bone mets in 2005-2009. Conclusions: Despite a high risk of SREs in pts with PC and bone mets, most such pts still do not receive IV BPs.
Phase I dose escalation trial of MVA-BN-PRO in men with nonmetastatic castration-resistant prostate cancer.
Authors: McLeod David G. , Adams George W. , Gittleman Marc C. , Bihartz David L. , Reiling Richard B. , Ruiz Henry E. , Cochran James S. , Prettyman Julie , Delcayre Alain , Godfrey Wayne R. , Legrand Fatema A. , Mann Grace , Bandman Olga
Published: February 2017

193

Background: MVA-BN-PRO is an investigational prostate cancer immunotherapy comprising of a highly attenuated non-replicating vaccinia virus engineered to encode prostate specific antigen (PSA) and prostate acid phosphatase (PAP) proteins. Preclinical studies in mouse tumor models demonstrated vaccine-mediated induction of anti-PSA and PAP specific immune responses and anti-tumor activity. Results of the open-label multi-center evaluation in subjects with non-metastatic castration resistant prostate cancer are presented. Methods: Eligible subjects had documented prostate cancer with a rising PSA while on androgen suppression therapy and were chemotherapy naïve. Three cohorts of subjects were immunized subcutaneously receiving either 1, 2 or 4 injections of study drug (1 injection = 1×108 tissue culture infectious dose, TCID50) at monthly intervals for three months (treatment). If the vaccinations were tolerated, re-treatment with an additional 3 monthly vaccinations was administered at the same dose. Responders, defined as subjects with stable or declining PSA at week 29 compared with baseline, were offered a 1-year extended treatment of up to 12 monthly vaccinations. Subjects were followed for one year after their last vaccination. The primary endpoint was safety. Immune responses (humoral and cellular) to MVA-BN-PRO including the transgenes PSA and PAP were assessed by the ELISA and ELISPOT assays, respectively. Exploratory analyses included anti-tumor activity as evaluated by serum PSA levels and progression by bone scan, per investigator determined, or death. Results: Twenty-four subjects were dosed. All subjects completed the initial 3 vaccinations (treatment) and 21 subjects received 6 vaccinations (re-treatment). Seven responders received additional vaccinations during the extended treatment. No dose-limiting toxicities were reported. There were no reported ≥ Grade 3 treatment-related adverse events (AE). The most common related AEs were Grade 1 or 2 general disorders and administration site reactions. Conclusions: MVA-BN-PRO was well tolerated. Results from immune analysis and clinical activity measured by PSA levels or radiological progression will be presented. Clinical trial information: NCT00629057.
Associations between single nucleotide polymorphisms (SNPs) in inflammation-related genes and quality of life after radiation therapy (RT) for prostate cancer.
Authors: Schoenfeld Jonathan D. , Margalit Danielle Nina , Shui Irene M. , Kasperzyk Julie L. , Sesso Howard D. , Martin Neil E. , Nguyen Paul Linh , Kantoff Philip W. , Rider Jennifer R. , Mucci Lorelei A.
Published: February 2017

2

Background: Prostate-directed RT results in local inflammation that may contribute to short-term toxicity and subsequently effects on long-term quality of life (QOL). We sought to explore the hypothesis that SNPs in inflammation-related genes may influence QOL sequelae following definitive prostate cancer RT. Methods: We studied Caucasian participants in the prospective US Physicians’ Health Study diagnosed and treated with RT for non-metastatic prostate cancer between 1982 and 2006. Forty-three SNPs in 10 inflammation-related genes were genotyped and analyzed using the additive model. Men were followed for cancer-specific QOL outcomes with regularly administered questionnaires. We dichotomized the maximum score for four parameters (decreased urinary stream, increased urinary frequency, rectal urgency and impotence) relevant to RT reported at least one year following RT and analyzed associations between scores and SNPs using Fisher’s exact tests and logistic regression. Results: We identified 264 men with QOL data who previously provided blood for genotype analysis and received RT at a median age of 72 years (IQR 68 – 76 years). Features at diagnosis included: 67% PSA<10, 61% Gleason<7, 95% T1/T2 disease and 71% Charlson co-morbidity index 0-1. QOL questions were completed a median of 6 years following RT. Without adjusting for multiple testing, 13 SNPs had nominally significant associations (p < 0.05) with QOL parameters; 7 remained significant after adjusting for age, features at diagnosis, and use of brachytherapy (Table). Conclusions: We identify candidate SNPs in inflammation-related genes that can be further explored in regards to their associations with long-term effects of prostate-directed RT. [Table: see text]
G-CSF utilization during abiraterone acetate (AA) and cabazitaxel (C) therapy: A retrospective U.S. claims analysis.
Authors: Mehra Maneesha , Stellhorn Robert , Ng Yvette , Todd Mary Beth
Published: February 2017

205

Background: AA and C are two recently approved therapies shown to extend survival in men with metastatic castrate-resistant prostate cancer (mCRPC) progressing after docetaxel treatment. The toxicity profiles of AA and C differ, and therefore it was hypothesized that the utilization of concomitant medications and supportive care measures, in particular G-CSF for the treatment of neutropenia, would differ as well. Methods: The Pharmetrics database (2008 to Jan 2012), a nationally representative, nonpayer-owned, integrated, commercial U.S. claims database, was used for this analysis. Eligible patients included those identified with a diagnosis of prostate cancer (ICD 9 code 185.X or 233.4) and a claim for either AA or C (identified by the appropriate NDC or J codes). Use of G-CSF was analyzed during treatment (defined as the period between the first claim to the last claim, full months inclusive) and also analyzed for the year prior to the first claim of either AA or C (index date). Results: 278 patients were identified with a claim for both cohorts. Median ages of patients in the two cohorts were similar (69 years in the AA cohort, 67.5 years in the C cohort). Docetaxel use in the year prior to the index date was 57% and 64% in the AA and C cohorts, respectively. The median duration of follow-up post-index date was 2.6 months in the AA cohort and 6.0 months in the C cohort. While the median number of prescriptions (3) was the same for the AA and C cohorts, the mean was slightly higher for C (4.4 vs 3.3). In the AA cohort, the use of G-CSF was as follows: 35% in the year before the index date and 3% during treatment. In the C cohort, the use of G-CSF was as follows: 42% in the year before the index date, and 67% during treatment. Conclusions: Based on this claims analysis, patients who received C were more likely to receive concomitant G-CSF vs patients who were receiving AA. This finding is consistent with the known risks/precautions relating to neutropenia as described in the TROPIC study for C. Prior to treatment, both cohorts had G-CSF use, which may be attributed to neutropenia during or following docetaxel therapy.
Efficacy and toxicity of q 2 weeks versus weekly versus q 3 weeks docetaxel in metastatic castration-resistant prostate cancer (CRPC).
Authors: Malhotra Akshiv , Poiesz Bernard J.
Published: February 2017

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Background: Standard treatment for metastatic CRPC is docetaxel 75 mg/m2q3weeks. Methods: We retrospectively studied patients treated with q 1, 2, or 3 weeks docetaxel regimens at 30, 60 and 75 mg/m2, respectively. The choice of regimen and duration of treatment was decided by their oncologist. Patients who had been in a clinical trial previously, or treated with any other chemotherapy before docetaxel were excluded. On this basis 41 patients were studied. Prostate specific antigen (PSA) was used as the primary method to assess response and progression. Response was a decline of >/=50% from baseline value with no clinical or radiographic evidence of disease progression. For patients whose PSA did not decrease, progression was a >/= 25% increase from baseline. If the PSA decreased without reaching response criteria, progression was a >/= 25% increase from nadir. In those who responded, progression was a >/= 50% increase from nadir. The increase had to be at least 5ng/ml. Toxicity was graded on the basis of CTCAE version 4.0. Response rate and toxicity in the 3 arms was compared using a two by two square t-test. Results: There were 12, 14, and 15 patients in the q1w, q2w and q3w arms, respectively. Response rates, mean progression free survival (PFS), median PFS, mean overall survival (OS), median OS, mean cumulative dose (MCD) and toxicity are shown in the Table. Three-year OS was 0%, 20%, and 0% in the q1w, q2w, and q3w arms, respectively. Toxicity was similar in the q1w, q2w, and q3w arms, except grade 1/2 neuropathy was higher in the q2w arm vs. the q1w arm (p=0.005). Conclusions: The MCD, response rates, PFS and OS in the q1w and q3w arms were similar to previously published reports. Patients in the q2w arm received a statistically significant higher MCD. Our data suggest a better outcome in the q2w arm as compared to the q1w and q3w arms. However, given the small number of patients studied, the results are not statistically significant. Toxicity was similar save for grade 1/2 neuropathy. [Table: see text]
Clinical outcomes and toxicity of estramustine phosphate (EP) addition to docetaxel (D) as first-line therapy for castration-resistant prostate cancer (CRPC): A cumulative analysis on 243 patients (pts) from two randomized phase II trials.
Authors: Caffo Orazio , Sava Teodoro , Zustovich Fable , Lodde Michele , Sacco Cosimo , Lo Re Giovanni , Buti Sebastiano , Basso Umberto , Gamucci Teresa , Facchini Gaetano , Perin Alessandra , Segati Romana , Russo Lucianna , Veccia Antonello , Galligioni Enzo
Published: February 2017

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Background: Although EP exerts a synergism with D and a meta-analysis suggested a survival advantage in combining EP to chemotherapy, D+EP combination is usually discouraged due to a marginal improvement in disease control at cost of an enhanced toxicity compared to D alone. In order to assess the role of EP added to D we have analyzed data from pts enrolled in two randomized trials with D ± EP conducted by our group (BJU Int 2008 – ASCO GU 2012). Methods: All patients received D 70 mg/m2IV q 3 wks ± E 280 mg/TID PO for 5 days starting 1 day prior to D. Ninety-five pts of the first study (started in 2002) were treated until progression; 148 pts of the second study received 8 D courses in continuous or intermittent fashion. We evaluated PSA response, PFS according to PCWG2, OS and toxicity. Results: We shared the clinical data from all 243 pts (123 D, 120 D+EP): the median baseline PSA values were 53 and 60 respectively; 49.5% and 59.1% of the D and D+EP pts presented visceral metastases, respectively. Clinical outcomes and main toxicities are summarized in the Table. Conclusions: The addition of EP to D was tolerable with a mild toxicity profile; it was able to double the biochemical responses which did not translate in any PFS or OS advantage. From our data the addition of EP addition to D should not further role in first line of CRPC, while it may help to overcome D resistance in selected cases according to our previously published data (Urol Oncol 2010). However, this statement should be critically considered at the light of new drugs availabile and active after D failure. Clinical trial information: 2006-005728-17. [Table: see text]
A pilot study of high-dose exisulind in men with biochemical relapse (BCR) of prostate cancer after definitive local therapy treated with intermittent androgen deprivation (IAD).
Authors: Yu Evan Y. , Kuo Kevin F , Hunter-Merrill Rachel , Gulati Roman , Cheng Heather H. , Flamiatos Jason Frederick , Gambol Teresa E , Hall Suzanne P , Higano Celestia S.
Published: February 2017

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Background: Exisulind is an apoptotic drug shown in vitro to inhibit expression and function of the androgen receptor. At lower doses as a single agent and in combination with chemotherapy it has demonstrated limited efficacy. In this pilot study, the potential for high dose exisulind to prolong the duration of the off treatment interval of IAD was studied. Methods: Eligible patients (pts) underwent prior definitive local therapy, had BCR, and received at least one full prior cycle of IAD, defined as a 9-month on- and variable off-treatment period (terminated by reaching PSA threshold 1 ng/mL for radical prostatectomy and 4 ng/mL for radiation). Exisulind (250 mg po bid) was started 3 months before completing the 2nd on-treatment period and continued through the 2nd off treatment interval and other IAD cycles until castration resistance (CRPC). We used a Cox proportional hazards model to estimate the association between receiving exisulind and time to resuming AD for pts who initiated exisulind during their 2nd on-treatment period. The model controlled for 1st off-treatment duration. Results: Nineteen pts were enrolled and treated with exisulind. Median age was 62 (range 50-75) years. Median PSA at diagnosis was 11 (3.9-99) ng/mL and 5 (1-19.2) ng/mL at initiation of IAD. Median Gleason score was 8 (6-9). Median duration of exisulind treatment was 1.5 (0.5-7.7) yrs and median follow-up was 9.3 (1.1-10.1) yrs. In 9 evaluable pts, taking exisulind was associated with a non-significant prolongation of the off treatment interval (15% decreased risk of progressing to PSA threshold and the next AD cycle, HR 0.85, 95% CI 0.41, 1.75, p=0.654). Six pts (32%) required at least one dose hold, 9 (47%) underwent a dose reduction for toxicity, and 7 (37%) came off trial for drug toxicity. Most common adverse events were elevated liver function tests (53%) and fatigue (42%). Median time to CRPC was 5.5 (0.3-not reached) yrs. Conclusions: High-dose exisulind was poorly tolerated and did not clearly extend the duration of 2nd off-treatment intervals compared to the 1st. More potent contemporary agents may be more beneficial in this setting. Clinical trial information: NCT00283803.
Time to follow-up and treatment in patients with newly diagnosed prostate cancer (PC) across clinical stages in an equal access health system.
Authors: Nallu Anitha , Mitikiri Nirupama Devi , Onukwugha Ebere , Mullins C. Daniel , Hussain Arif
Published: February 2017

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Background: The purpose of this pilot study is to describe the time interval from diagnosis to initial specialist visit and treatment initiation in pts with newly diagnosed PC across different clinical stages (S1- 4) in an equal access system such as a Veterans Affairs Medical Center (VAMC). Methods: Data from the Baltimore VAMC database were used to examine pts diagnosed with PC in 2010 to assess variation across different clinical stages with respect to follow up with specialists, diagnostic tests and treatment initiation during the year following diagnosis. Specialists include urologists, medical oncologists and radiation oncologists. Diagnostic tests included CT and/or bone scans. Treatments based on clinical staging included active surveillance, radical prostatectomy, external beam radiation therapy, brachytherapy, androgen deprivation therapy, chemotherapy or enrollment into clinical trials. Results: One hundred and nine pts were diagnosed with PC at the BVAMC in 2010. All but one patient had follow-up with a specialist after positive prostate biopsy. Majority of pts in each stage saw more than one specialist (S1-50%, S2-74%, S3-60%, S4-82%). The median number of days to first follow up visit with a specialist was similar across all stages (S1-16 d, S2-15 d, S3-17 d, S4-14 d). Four out of the 109 pts were lost to follow up. S4 pts were initiated on treatment at a median of 26 days after diagnosis, whereas S1, S2 and S3 pts were initiated on treatment at a median of 151,100 and135 days respectively, after diagnosis. Pretreatment CT scan and/or bone scans were done in S1-38%, S2 -70%, S3-80% and S4-100% pts. Conclusions: The results of this pilot study showed that while time to initial follow up visit after diagnosis of PC does not differ across the clinical stages, treatment for S4 pts is initiated much earlier than for the other stages. It will be of interest to determine whether these patterns hold for other years and in other VA Medical Centers.
Is routine prostate biopsy needed prior to radical cystectomy?
Authors: Hashimoto Yasuhiro , Suzuki Yuichiro , Imai Atsushi , Okamoto Akiko , Yamamoto Hayato , Hatakeyama Shingo , Yoneyama Takahiro , Koie Takuya , Ohyama Chikara
Published: February 2017

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Background: Prostate cancer (Pca) can be detected coincidentally in radical cystoprostatectomy (RCP) specimens for invasive bladder cancer. However, there is no uniformity of opinion on the need for prostate biopsy prior to RCP. We evaluated the necessity of preoperative prostate biopsy in invasive bladder cancer. Methods: From 1998 through 2009, of 300 patients undergoing radical cystectomy for muscle-invasive bladder cancer, 252 were male. Of these, we focused 212 patients, whose prostate-specific antigen (PSA) was measured preoperatively. Results: The median age was 66years and median follow-up period was 46 months. Thirty-five patients with PSA > 4.0 ng/mL or digital rectal examination (DRE) positive were all subjected to transrectal ultrasound (TRUS)-guided prostate biopsy (Pbx), and Pca was detected in 7 cases (20%) (Group I). Pca was also detected in 5 patients (17.9%) in RCP specimens of the 28 whose Pbx results were negative (Group II). Seventy-seven of the 177 patients with PSA ≤ 4.0ng/mL and DRE negative were underwent TRUS-guided Pbx, and Pca was detected in 1 case (1.3%) (Group III). Pca was detected in 10 patients (13.2%) out of the 76 whose Pbx results were negative (Group IV). Of the 177 patients, 100 underwent RCP without prostate biopsy, and Pca was detected in 16 cases (16%) (Group V). The average Gleason score of each Group, I, II, III, IV, and V were 6.6, 6.6, 7, 6.2, and 6.5, respectively. Tumor volumes of each Group, I, II, III, IV, and V were 3.12mL, 1.0mL, 0.65mL, 0.43mL, and 0.19mL, respectively. No patients experienced recurrence of PC, including biochemical recurrence. Conclusions: In cases with PSA ≤4.0 ng/mL and/or DRE negative, Pbx is not considered necessary. In cases with PSA > 4.0 ng/mL or DRE positive, Pca with an average volume of 3.12 mL were detected by Pbx in 20% of the patients. However, most are localized Pca, and postoperative recurrence of the Pca is not seen during follow-up period. The question of whether all patients in this group require Pbx needs to be examined through further stratification.