bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of hypofractionated high-dose intensity-modulated radiotherapy schedules for prostate cancer: Results from the phase III randomized CHHiP trial (CRUK/06/016).
Authors: Dearnaley David P. , Syndikus Isabel , Mossop Helen , Birtle Alison J. , Bloomfield DJ , Cruickshank Clare , Graham John , Hassan Shama , Khoo Vincent , Logue John P. , Mayles Helen , Money-Kyrle Julian , Naismith Olivia Frances , Panades Miguel , Patterson Helen , Scrase Christopher D , Staffurth John , Tremlett Jean , Griffin Clare , Hall Emma
Published: February 2017

2

Background: We aimed to explore the dose response relationship for two 3 Gray (Gy) hypofractionated radiotherapy (hRT) schedules for localised prostate cancer (PCa). Methods: hRT schedules of 60Gy/20 fractions (f) and 57Gy/19f were compared with conventional RT (cRT) 74Gy/37f; iso-effective for alpha-beta ratios of 2.5Gy and 1.5Gy respectively. The trial was powered to demonstrate non-inferiority between each hRT schedule and cRT, with 3,213 patients (pt) needed to rule out 5% inferiority (80% power, 1-sided alpha 5%) assuming 70% event-free rate in cRT, corresponding to a critical hazard ratio (HR) of 1.21. The trial was not formally powered to directly compare the two hRT schedules. Pt with N0 T1b-T3a localised PCa were randomized (1:1:1 ratio). The primary endpoint was PCa progression (freedom from biochemical failure by Phoenix consensus guidelines or PCa recurrence). Acute toxicity was assessed up to 18 weeks post treatment and late side effects to 5 years (yr) by RTOG, LENT-SOM and patient reported outcomes (PROs). Results: 3,216 pts were randomized between 2002 and 2011; 1,065 (74Gy), 1,074 (60Gy), 1,077 (57Gy). Baseline characteristics were well balanced across groups: median age 69 yr; NCCN risk group 15% low, 73% intermediate, 12% high. With median follow up 5.2yr, 5yr progression-free rate (95% CI) was 74Gy: 88.3% (86.0%, 90.2%); 60Gy: 90.6% (88.5%, 92.3%), 57Gy: 85.9 (83.4, 88.0); HR60/74: 0.83, 90% CI (0.68, 1.03), HR57/74: 1.20, 90% CI (0.99, 1.45). Significantly more events were observed with 57Gy compared to 60Gy; HR57/60: 1.44, 90% CI (1.18, 1.75), log-rank p=0.003. No significant difference in acute RTOG bladder or bowel toxicity was observed between hRT schedules. Late toxicity profile was favorable; with grade 2+ RTOG bladder (60Gy: 16/960 (1.7%); 57Gy: 11/962 (1.1%), p=0.34) and bowel (60Gy: 28/960 (2.9%); 57Gy: 17/962 (1.8%), p=0.10) toxicity at 2yr. Analysis of LENT-SOM and PROs supported these results. Conclusions: With 5 yr follow-up treatment with a 3Gy schedule of 60Gy/20f shows improved treatment efficacy compared to 57Gy/19f and is non-inferior to 74Gy/37f with a similar low level of acute and late normal tissue damage. Clinical trial information: ISRCTN97182923.
Novel agents’ sequencing following first-line docetaxel in mCRPC patients: CAPRO study.
Authors: Puente Javier , Gonzalez del Alba Aranzazu , Sala Nuria , Méndez-Vidal María José , Pinto Alvaro , Rodriguez Sanchez Angel , Cuevas Sanz Jose Miguel , Guma Josep , Borrega Pablo , Molins Carmen , García Domínguez Rocío , Basterrechea Laura , López Jiménez Antonio , Gonzalez-Billalabeitia Enrique , Crespo Guillermo , Domenech Montserrat , Cabrera Suárez Miguel Ángel , Luque Raquel , Ruiz Pedro , Vazquez-Estevez Sergio
Published: February 2017

229

Background: Novel agents, such as abiraterone (A), cabazitaxel (CZ), and enzalutamide are currently available for the treatment of docetaxel (D)-treated metastatic castration resistant prostate cancer (mCRPC). The sequencing approach following D progression is still unknown. We now explore which factors are driving sequencing decisions in routine clinical practice in Spain. Methods: A prospective multicenter national observational descriptive study collecting data of 2nd line (L) treatments in mCRPC patients to analyze responses and progression to 1stL D. Results: 149 patients have been recruited from July 2013 to January 2015. Median age was 72 (48-89). Median D cycles was 6 (1-24), and median dose: 75 mg/m2 (30-75). 24 patients (16%) required dose reduction. The reasons for D ending were treatment completion (40%, n = 60), toxicity (15.3%, n = 23), progression (radiological, biochemical, clinical; 42%, n = 63), or others (2.7%, n = 4). 67% (n = 100) of the patients received A, 25% (n = 44) CZ, and 8% (n = 5) other treatments as 2ndL. From those who completed or progressed to D (n = 123), 2ndL initiation was mainly determined by two progression criteria (2C; biological and radiological), followed by one progression criteria (1C). This was independent of the 2ndL treatment chosen, and it was observed in similar ratios in both A (2C: 50%, n = 39; 1C: 37.2%, n = 29) and CZ (2C: 62.5%, n = 25; 1C: 27.5%, n = 11). Nevertheless, A was predominantly given when patients progressed after D ending, whereas CZ was mostly given when progressing during D (Table 1). Conclusions: A is the 2ndL treatment of choice in routine clinical practice in Spain, independent of the type and time of progression. CZ is preferentially used in patients progressing during D treatment. [Table: see text]
Pre-clinical rationale for combination PI3K and BRD4 inhibition in advanced prostate cancer.
Authors: Toren Paul , Zoubeidi Amina , Allman Jared
Published: February 2017

234

Background: The PI3K/Akt pathway is frequently activated in aggressive and resistant prostate cancer. Here we detail our pre-clinical evaluation of AZD8186, a novel β and δ selective PI3K small molecule inhibitor. Further, we investigate how increased transcription of the myc oncogene may represent a mechanism of resistance to monotherapy PI3K/Akt inhibition. Therefore, we further evaluated co-targeting strategies against both the PI3K/Akt pathway and the epigenetic reader protein BRD4. Methods: Human prostate cancer cell lines LNCaP and 22RV1 were tested for sensitivity to AZD8186 in vitro. Caspase-3 activity and flow cytometry were used to assess apoptosis. Western blotting and RT-qPCR were used to measure AR and myc pathway genes and protein expression. Castrate resistant LNCaP xenografts were treated with 10mg/kg and 25mg/kg doses of AZD8186 given orally 4 days on, 3 off. Results: In vitro results demonstrated sensitivity to AZD8186 with decreases in cell proliferation and increases in apoptosis. In vivo results demonstrated a dose-dependent decrease in tumor growth velocity with AZD8186 with on-target decreases in pAkt was observed in xenograft tumour samples. Further, increases in myc protein and mRNA levels were seen in xenograft samples treated with AZD8186 compared to control. Downstream increases in EGFR and IGF-IR mRNA transcripts induced by AZD8186 were also seen in vitro and in vivo. Increases in myc, EGFR and IGF-IR was also seen in cells and tumours treated with an Akt inhibitor. Addition of the BDR4 inhibitor JQ1 decreased the increase of myc induced by AZD8186 and also partially abrogated the increases in EGFR, IGFR. Greater suppression of PSA expression was seen with the combination of AZD8186 and JQ1 compared to AZD8186 and enzalutamide. Similar results were seen in the 22RV1 cell line. Conclusions: Inhibition of PI3K with AZD8186 inhibits growth of PTEN-negative LNCaP cells. However, feedback activation of myc and AR pathways occurs. We demonstrate BRD4 inhibition using JQ1 which co-targets both myc and AR feedback pathways as a rationale combination strategy with PI3K inhibition. This strategy warrants further investigation in prostate cancers with an activated PI3K/Akt pathway.
Bipolar androgen therapy (BAT) in men with hormone sensitive (HS) prostate cancer (PC).
Authors: Schweizer Michael Thomas , Wang Hao , Luber Brandon , Nadal Rosa Maria , Spitz Avery N. , Rosen David Marc , Cao Haiyi , Antonarakis Emmanuel S. , Eisenberger Mario A. , Carducci Michael Anthony , Paller Channing Judith , Denmeade Samuel R.
Published: February 2017

236

Background: We documented a paradoxical anti-tumor effect when castration-resistant prostate cancer patients were treated with intermittent, high-dose testosterone (i.e. BAT) [PMID: 25568070]. Since the adaptive increase in androgen receptor expression that follows chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with HS PC would also respond to BAT if given following a 6-month ADT lead-in. Methods: Men with asymptomatic HS PC and low metastatic burden (N = 20) (no visceral disease, ≤ 10 bone metastases, no lymph nodes > 5 cm short axis diameter) or non-metastatic biochemically recurrent disease (N = 13) were enrolled. Following 6-months of ADT, those with a PSA < 4 ng/ml went on to receive 2 cycles of BAT. A cycle of BAT was defined as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29 and 57 followed by ADT alone D 85-169. ADT was continued throughout the study to allow for rapid cycling from near castrate to supraphysiologic range T following T injections. The primary endpoint was the percent of patients with a PSA < 4 ng/ml after 2 cycles of BAT, with the study designed to reject a null rate of 40% at a one-sided alpha = 0.1. Secondary endpoints included quality of life (QOL) as measured by the SF-36, FACT-P, IIEF and IPSS surveys. Results: Twenty-nine of 33 patients received BAT following the ADT lead-in (1 withdrew consent, 3 had PSA > 4 ng/ml). The primary endpoint was met, with 17/29 men (59%, lower bound 90% confidence interval = 45%) having a PSA < 4 ng/ml after 2 cycles of BAT. Ten patients receiving BAT had RECIST evaluable disease, and 8 (80%) objective responses were observed (4 complete; 4 partial). Three patients progressed per RECIST criteria and 3 had unconfirmed progression on bone scan. Men treated with 6-months of ADT had improved QOL after the first cycle of BAT. The median improvement in SF-36, FACT-P, and IIEF total scores were 3.2 (range, -20 to 48; P = 0.21), 3.5 (range, -30 to 50; P = 0.04), and 10 (range, -4 to 59; P < 0.001) points, respectively. There was no change in total IPSS score (median change 0 [range, -9 to 8; P = 0.87]). Conclusions: BAT demonstrated preliminary efficacy in men with HS PC following 6-months of ADT. BAT may improve QOL in men that have received ADT. Clinical trial information: NCT01750398.
Association of androgen receptor V9 (ARV9) mRNA expression in metastatic tissue with early resistance to pre-chemotherapy abiraterone acetate/prednisone (AA/P).
Authors: Kohli Manish , Hillman David W. , Carlson Rachel , Wang Liguo , Li Ying , Tan Winston , Ho Thai Huu , Sicotte Hugues , Wang Liewei , Costello Brian Addis , Pitot Henry C. , Quevedo Fernando , Dronca Roxana Stefania , Moynihan Timothy Jerome , Atwell Thomas D , Eiken Patrick W , McMenomy Brendan P , Bryce Alan Haruo , Wu Kevin , Dehm Scott
Published: February 2017

237

Background: AA/P is an approved treatment for mCRPC but there are no known predictive markers of response or resistance. We conducted a prospective trial to evaluate if Androgen Receptor (AR) & AR-variant (ARV) expression in tissue metastases can predict resistance to AA/P. Methods: mCRPC stage patients (pts) initiating pre-chemo AA/P underwent metastatic site biopsies prior to (pre-AA/P) and after 12 weeks of treatment. Composite progression at 12 weeks, (primary endpoint) was evaluated with PSA, RECIST, bone scan and symptoms (per PCWG2). mRNA expressions of pre-AA/P ARFL, ARV3, ARV7, ARV9, ARV23, ARV45, four cell cycle division genes, Chromogranin-A (CHGA) together with PSA/testosterone levels, Gleason Score (GS) at initial diagnosis; high versus low volume disease; time from starting hormone therapy to mCRPC stage and serum CHGA levels were evaluated using a logistic regression model for predicting resistance at 12 weeks of therapy. A final multivariate model fitted only those factors thought to be clinically relevant or with an entry threshold of p ≤ 0.3 in univariate analysis. Results: Between 6/2013 & 3/2015, 82 pts were enrolled of which 52 had complete mRNA expression & disease assessment data at the12-week time point for analysis. Median age of the cohort was 72.5 yrs (IQR: 68.5-78); median pre-AA/P PSA was 18 ng/ml (IQR: 8.1- 46.6); GS distribution at initial diagnosis for GS 2-6; 7; 8-10 was 11; 14; 27 respectively. Progression was observed in 21/52 pts after 12 weeks. At the univariate level elevated pre-AA/P expression of ARV3 (p = 0.08), ARV7 (p = 0.26), ARV9 (p = 0.04), and cell division cycle gene CDC45 (p = 0.19) along with GS at diagnosis (p = 0.29) met the threshold for inclusion into multivariate analysis. Elevated expression of pre-therapy ARV9 in metastases alone was associated with progression at 12 weeks (OR: 3.9; CI 1.07 – 14.16; C-Index: 0.63). The 12-week biopsy of pts with progression had increased ARV9 mRNA expression compared to pts responding at 12 weeks (p = 0.14). Conclusions: Increased ARV9 mRNA expression in metastases is associated with early resistance to AA/P. This observation will need further validation in comparable datasets. Clinical trial information: NCT #0195364.
Pilot study of clinical targeted next generation sequencing for prostate cancer: Consequences for treatment and genetic counseling.
Authors: Cheng Heather H. , Klemfuss Nola , Montgomery Robert B. , Higano Celestia S. , Schweizer Michael Thomas , Mostaghel Elahe A. , Yu Evan Y. , Nelson Peter , Pritchard Colin C.
Published: February 2017

251

Background: Targeted next generation sequencing (NGS) panels for identification of actionable mutations are increasingly used in oncology for therapeutic decision-making, but have yet to be widely used for prostate cancer.To determine the utility of applying a targeted next generation sequencing to prostate cancer management, we conducted a pilot study using the clinical molecular diagnostic assay, UW-OncoPlex, on primary and metastatic tumors from patients with prostate cancer. Methods: Patients receiving treatment for prostate cancer by a medical oncologist were eligible. After providing informed consent, tumor DNA was extracted from formalin-fixed, paraffin-embedded (FFPE)primary tumors and/or metastatic biopsies. Extracted DNA was analyzed using UW-OncoPlex, a targeted NGS panel designed to assess genomic alterations in 234 cancer-associated genes (PMID: 24189654). Results were discussed at a monthly multidisciplinary precision tumor board prior to communicating results to patients. Results: Forty patients consented to the study and 31 (78%) had reportable results. Findings included frequently observed prostate cancer genomic aberrations, including: TMPRSS2-ERG fusions and copy-number alterations of PTEN, TP53, FOXA1, AR, and SPOP. We also observed potentially actionable alterations in BRAF, MAP2K1 (MEK1), PIK3R1, MET, FGFR1, and FGFR3, which inform future treatment and clinical trial considerations. Notably, 8/31 (25%) patients had suspected high penetrance germline mutations, including in BRCA2 (N = 3), TP53 (N = 2), ATM (N = 1), and CHEK2 (N = 2). These 8 individuals were referred to medical genetics and 7 of 8 mutations were confirmed to be germline. One patient was found to have a hypermutated phenotype associated with bi-allelic MSH6 mutation and microsatellite instability. Conclusions: Targeted NGS panel testing may be useful in informing future treatment approaches and clinical trial selection for patients with prostate cancer. In addition, we observed a high proportion of cases with suspected high-penetrance germline mutations and immediate actionability through referral to medical genetics.
Understanding prostate cancer survivorship relative to co-habitation.
Authors: Mitteldorf Darryl
Published: February 2017

253

Background: Studies suggest that married men diagnosed with prostate cancer survive longer than single men. None of the published research shows why this might be the case. Nothing is known about how treatment choice satisfaction and aspects of the psycho-social experience might differ between single and married men. Our aim was to understand if there are any differences in key indicators which might influence survivorship between single and married or partnered men. Methods: 1,762 men diagnosed with prostate cancer completed a lengthy online survey during a one month in 2014. The men were randomly selected from a national Prostate Cancer support group network. We investigated compliance and satisfaction in their treatment choices, activities of life satisfaction, spirituality and overall life sentiment. We included questions relating to the length of time between diagnosis and the survey and the size and location of the respondents community. We stratified each question by whether or not a person lived alone or was married or partnered or lived in some other communal situation. Results: There were no significant differences in diagnosis years by living status. A higher proportion of people with prostate cancer who live alone get more than 3 days per week strenuous exercise than those who live in communal situations. 20.26% of men who live alone exercised seven days, while only 14.24% of the married/partnered group exercised as much We used the CORR procedure in SAS to determine if a correlation existed between answers to specific questions and whether or not a person lived alone. Very few response patterns were correlated with being alone. No question in the survey was able to produce a correlation greater than 0.31. A feeling of loneliness was most correlated with being alone (r = 0.302). Trouble urinating (r = 0.24134) and trouble moving one’s bowels (r = 0.16904) were also mildly correlated with being single. Conclusions: Our study shows that being married, partnered or single is irrelevant to prostate cancer survivorship. Our results suggest that we have to look for reasons unrelated to personal relationships and household composition to understand why married men diagnosed with prostate cancer hold a longevity advantage over single men.
Mapping prostate cancer (CaP) recurrence after prostatectomy with c-11 choline PET/CT and 3T pelvic MRI in the contemporary era.
Authors: Sobol Ilya , Haloi Rimki , Park Sean Sunghun , Viers Boyd , Davis Brian , Mynderse Lance A , Boorjian Stephen A. , Thompson Robert Houston , Tollefson Matthew K. , Gettman Matthew , Quevedo Fernando , Froemming Adam , Lowe Val J. , Frank Igor , Karnes R. Jeffrey , Kwon Eugene D.
Published: February 2017

255

Background: The purpose of this study was to identify site-specific recurrence patterns for patients (pts) with biochemical recurrence (BCR) after prostatectomy (RP) using C-11 Choline PET/CT (C11Ch) and 3T pelvic MRI with endorectal coil (pMRI). Methods: Between 2008 and 2006, 2,466 men underwent C11Ch and pMRI for BCR after RP. From this cohort, we identified 261 pts who received no adjuvant or salvage therapy (androgen deprivation or radiation). Suspected radiographic relapse was confirmed by biopsy (46%) or progression/response to treatment in concordance with subsequent rise/decline in PSA (54%). Results: Of the 261 men evaluated, 202 (75%) had positive pMRI, C11Ch or both. Seventy nine (39%), 105 (52%) and 18 (9%) pts had high, intermediate, and low risk CaP, respectively at RP. Median PSA at the time of positive scan was 2.3 ng/mL, with a median time from BCR to radiographic disease identification of 15 months. Of these 202 men, 67 (33%) harbored prostate fossa recurrence only, 44 (22%) had a combination of local and metastatic disease and 91 (45%) had metastatic disease without local recurrence. Forty (20%) pts had pelvic nodal recurrence only and 18 (9%) had perirectal nodal involvement. Median PSA for pts with local only recurrence, distant metastases only, and local + distant disease was 2.3, 2.7 and 2.2 ng/mL, respectively, with a median interval from BCR to positive scan of 16.7, 7.9 and 11 months. Imaging revealed that 33% to 66% of our cohort would have all sites of disease treated by salvage RT depending on the extent of the treatment field Conclusions: C11Ch and pMRI were used to identify recurrence patterns in pts with BCR after RP only. At median PSA of 2.3 ng/ml, our study demonstrates a low rate of local-only recurrence, higher than anticipated frequency of metastatic recurrence with peak frequency within the pelvic lymph nodes, and substantial perirectal recurrences. Despite the high rates of distant recurrences, 2/3 of our cohort had their disease limited to the pelvis and could be potential candidates for local therapies, including salvage radiation.
Is salvage focal cryotherapy curative treatment for patients with localized recurrent prostate cancer?
Authors: Katz Aaron , Kosinski Kaitlin E. , Berg Courtney
Published: February 2017

26

Background: The salvage therapy options for patients with recurrent unilateral prostate cancer after primary radiation, or cryotherapy, are limited. Salvage focal cryotherapy is becoming a more popular treatment option as it has shown success in its disease-free survival rates. Salvage focal cryotherapy enables patients to delay or negate the use of hormone therapy, which has many unfavorable adverse effects. The aim of this study is to report on the curative success of salvage focal cryotherapy in patients with recurrent unilateral prostate cancer. Methods: We identified patients who underwent salvage focal cryotherapy at Winthrop University Hospital between February 2011 and August 2015. Age at the time of treatment, follow-up time, nadir PSA levels, and follow-up treatments were assessed. Results: From 2011 to 2015, 88 patients underwent salvage focal cryoablation. Of these patients, 14 (15.9%) required another therapy treatment after salvage focal cryoablation. Hormone therapy was a necessary treatment for 9 patients. Only 6 patients (6.8%) went on to hormone therapy due to an MRI finding of a local, nodal, or distant relapses. Three (3.4%) patients went on to hormone therapy due to a rise in PSA. Conclusions: Focal salvage therapy is associated with very low risk of clinical and radiographic progression of cancer. In our patients with radiation recurrent cancer, we were able to prevent or delay the use of hormone therapy in the majority of these men. [Table: see text]
A randomized trial of abiraterone acetate (AA) administered with 1 of 4 glucocorticoid (GC) regimens in metastatic castration-resistant prostate cancer (mCRPC) patients (pts).
Authors: Attard Gerhardt , Merseburger Axel S. , Sternberg Cora N. , Cerbone Linda , Recine Federica , Jones Robert J. , Feyerabend Susan , Berruti Alfredo , Joniau Steven , Schatteman Peter , Geczi Lajos , Tenke Peter , Werbrouck Patrick , Lefresne Florence , Nave Shelby Florence , Lahaye Marjolein , Pick Corinna , Tombal Bertrand F.
Published: February 2017

261

Background: AA is approved for mCRPC, coadministered with prednisone (P) (5 mg BID) to prevent adverse events (AEs) associated with mineralocorticoid excess (ME). Lower GC doses had not previously been formally evaluated in combination with AA. Methods: This was an open-label, multicenter, phase 2 trial (NCT01867710) of asymptomatic chemotherapy-naïve mCRPC pts randomized 1:1:1:1 to AA (1000 mg QD) plus P 5 mg BID or P 5 mg QD or P 2.5 mg BID or dexamethasone (DEX) 0.5 mg QD. Pts who had previously received GC or ketoconazole were excluded. The primary end point was no ME (% of pts experiencing neither hypokalemia nor hypertension during the first 24 weeks of treatment).Secondary end points included additional safety, as well as response rate in the first 24 weeks, defined as a decline in prostate-specific antigen (PSA) ≥ 50% confirmed after 4 weeks. Results: 164 pts were randomized; 133 (81.6%) completed 24 weeks’ treatment. Median age: 70 years. Table 1 shows the rates of ME, hypertension, hypokalemia and PSA response. Changes in HbA1c values were minimal and observed in 16 (10.7%) pts. Conclusions: These data suggest that P 5 mg BID, which is approved in combination with AA, and DEX 0.5 mg QD, are effective in preventing ME-associated AEs, and that P 2.5 mg BID and P 5 mg QD can be safely used with appropriate monitoring. The suggestion of a higher PSA response rate with DEX 0.5 mg QD arm warrants further validation. Clinical trial information: NCT01867710. [Table: see text]
Quality-adjusted survival comparison between androgen deprivation with radiation therapy versus radiation therapy alone for locally advanced prostate cancer: Decision analysis from RTOG 85-31 trial.
Authors: Jeong Chang Wook , Ahn Soyeon , Lee Minjung , Ku Ja Hyeon , Kwak Cheol
Published: February 2017

265

Background: Radiation Therapy Oncology Group (RTOG) trial 85-31 has shown that addition of androgen deprivation therapy to radiation therapy (RT+ADT) for patients with locally advanced prostate cancer benefits local control and progression-free survival compared to RT alone. However, the survival gain may be diluted with increased toxicity of hormone manipulation. There is a need to develop new decision analysis methods to incorporate survival time and quality of life (QoL) adjusting for various health states and persistent complications. Methods: We previously developed “quality-adjusted survival analysis using duration” (QASAD) and “quality-adjusted survival analysis using probability” (QASAP) to estimate quality-adjusted survival time. The QASAD uses the median duration in each state to weight the utilities, while the QASAP uses the proportional probability of being in each state for weighting. The survival and complication rates of RTOG 85-31 were reconstructed based on published Kaplan-Meier survival curves, and the utility values for states were obtained from the literature. Probabilistic sensitivity analysis was applied using Monte Carlo simulation with 1000 simulated samples. Results: QASAD and QASAP showed that the quality-adjusted life year (QALY) values in RT+ADT were generally higher than those in RT. In probabilistic sensitivity analysis, QASAD resulted in 4.93 (95% bootstrapped confidence interval [CI] = 4.12 to 5.71) for RT and 5.60 (95% CI = 4.30 to 6.48) for RT+ADT. QASAP resulted in 4.85 (95% CI = 4.16 to 5.39) for RT and 4.96 (95% CI = 3.73 to 5.78) for RT+ADT. Conclusions: The decision analyses showed that RT+ADT provided slightly better quality-adjusted survival outcome after treatment than RT alone. The QASAD and QASAP methods may help the decision of optimal treatment balancing between survival gain and unfavorable quality of life. [Table: see text]
Phase Ib trial of docetaxel, prednisone, and pazopanib, in men with metastatic castration resistant prostate cancer (mCRPC).
Authors: George Daniel J. , Halabi Susan , Healy Patrick , Gemberling Sarah , Winters Carolyn , Mundy Kelly , Harrison Michael Roger , Szmulewitz Russell Zelig , Armstrong Andrew J.
Published: February 2017

275

Background: Docetaxel prednisone (DP) is a standard of care for men with metastatic castrate resistant prostate cancer (mCRPC) with median progression-free survival (PFS) of 4-6 months and overall survival (OS) of 19 months, supporting a need for further treatment options. Pazopanib (PAZO) is a multi-targeted kinase inhibitor of VEGF receptors approved for treatment of kidney cancer and sarcoma. We performed a two center, Phase Ib study of DP + PAZO to evaluate the safety and early efficacy in mCRPC. Methods: This is a 2 site phase 1 DOD Prostate Cancer Clinical Trials Consortium trial of DP + PAZO once daily with ongoing ADT in men with mCRPC. The primary endpoint was safety; secondary endpoints included evaluation of a maximum tolerated dose (MTD) through a dose escalation and expansion design, pharmacokinetic assessments, PSA and radiographic responses, and toxicity. Results: Twenty-five men were treated over 6 dose levels using a 3+3 design. Pegfilgrastim (Neu) was added to the regimen after myelosuppression limited dose escalation. With Neu, our target MTD of D 75 mg/m2; P 10 mg QD and PAZO 800 mg QD was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. 17 patients had received prior Abi and/or Enza. The most common AEs were alopecia (86%), fatigue (69%), diarrhea (58%), and nausea (53%), and the most common Grade 3-5 SAEs were neutropenia (33%) and leukopenia (19%). Three deaths attributed to study treatment occurred: one from pneumonitis, one from respiratory failure, and one from intracranial hemorrhage. The proportion of 30%, 50% and 90 % PSA declines were 69%, 58% and 25%, respectively. The objective response rate was 31% (11/36). Median PFS was 18.6 months (95% CI: 6.5, 27.7) and OS was 22.2 months (95% CI: 14.7, -). Predicted median OS using the Halabi nomogram was 20.9 months (95% CI: 19.2, 23.0) with 23%, 34% and 43% of patients in low, intermediate and high risk groups, respectively. Conclusions: DP + PAZO (with Neu) were tolerable at full doses and demonstrated a surprisingly long PFS and high objective response rate in a relatively poor risk group of mCRPC patients. These data support further randomized studies of DP + Pazo in Abi/Enza refractory patients. Clinical trial information: NCT01385228.
[18F]NaF PET/CT imaging biomarkers of progression-free survival in metastatic prostate cancer.
Authors: Harmon Stephanie , Perk Tim , Eickhoff Jens C. , Staab Mary Jane , Choyke Peter L. , Dahut William L. , Apolo Andrea B. , Humm John , Larson Steven M. , Morris Michael J. , Perlman Scott , Liu Glenn , Jeraj Robert
Published: February 2017

277

Background: 18F-Sodium Fluoride (NaF) PET/CT has been shown to be superior to 99mTc-MDP SPECT in detection of bone metastases and shows great promise to reliably measure functional changes in bone. This study assesses the relationship of Progression Free Survival (PFS) with NaF PET/CT measures in patients with metastatic Castration-Resistant Prostate Cancer (CRPC). Methods: 55 CRPC patients had NaF PET/CT scans performed at baseline, which was repeated at week 9 if receiving taxane-based therapy (N = 16) or week 12 if receiving androgen-signaling pathway (AR) inhibitors (N = 39). Bone lesions were identified using a novel technique allowing for extraction and tracking of PET metrics from individual lesions at every timepoint. Cox proportional hazard regression analyses were conducted to evaluate associations between imaging metrics and PFS. Results: Median PFS was 8.3 months (range 1.0-30.3+). The strongest predictor of PFS in univariate analysis was total functional burden (SUVtotal) (P < 0.0001) during treatment for all patients. Predictors of PFS differed between both treatment cohorts of patients (Table 1), including number of lesions, fraction of skeletal involvement, and average lesion activity (SUVmean). Maximum PSA benefit (percent decrease) during the first 12 weeks of therapy was highly predictive of PFS in the AR-directed cohort of patients (HR = 1.012 , P = 0.0005), as was change in the number of lesions (HR = 1.01, P = 0.03). Conclusions: There is indication thattotal functional burden of disease during treatment with taxane or AR-directed therapy is a strong predictor of PFS. In addition, change in number of lesions was predictive of treatment efficacy. This supports ongoing development of NaF PET/CT based imaging biomarkers in mCRPC. Clinical trial information: NCT01516866. [Table: see text]
Outcomes and patient-related reported urinary toxicity of low dose rate brachytherapy for localized prostate cancer.
Authors: Meeks Marshall , Michalski Jeff M. , Markovina Stephanie Subasic , DeWees Todd A.
Published: February 2017

29

Background: Brachytherapy (BT) is a common treatment modality for localized prostate cancer (LPCa). Here we report our institutional outcomes and patient-reported genitourinary (GU) toxicity following BT for LPCa. Methods: Medical records of patients with LPCa treated with low dose rate (LDR) BT at our institution from 1997-2011 were reviewed. BT prescriptions were 145 Gray (Gy) and 109Gy for mono- and combined iodine 125 (125I) therapy, and 125Gy and 100Gy for mono- and combined palladium 103 (103Pd) therapy. Biochemical failure was defined by the Phoenix definition. Kaplan Meier curves were used to compare biochemical relapse-free survival (bRFS), metastasis-free survival (MFS), and overall survival (OS). Patient-reported GU toxicity was evaluated by the American Urological Association Symptom Score (AUAS), and results binned into three time intervals, 1, 6, and 12 months post-BT. Repeated measures analysis determined a trend in AUAS score over time. Effect of age as a continuous variable, prostate specific antigen, Gleason score, clinical T stage, combined external beam radiotherapy + BT and use of neoadjuvant androgen deprivation therapy (nADT) on AUAS score was determined. Results: Of 459 patients identified, 400 received BT monotherapy and 8% received nADT. Median follow-up was 5.8 years. Nine-year bRFS, MFS, and OS were 92.8%, 97.9%, and 79.7%. Pretreatment AUAS scores were available for 252 patients. For 69 patients with all four values, median baseline AUAS scores rose from 6 to 14 at one month following BT (p < 0.0001). AUAS scores did not change from one-month to 6 months post-BT (p = 0.99), but decreased to a median of 8 (p < 0.0001) by 12 months post-BT. In the 69 patients with all values, no factors were found significant for change in AUAS scores. For 252 patients with pre-treatment AUAS and at least one additional value (assuming values missing at random), analysis revealed older age and use of nADT were associated with higher AUAS scores at all time points. Conclusions: LDRBT for LPCa offers excellent bRFS, MFS, and OS. AUAS scores rose in the first 6 months following BT but returned to pre-treatment baseline by 12 months post-BT. Older age and nADT use may be associated with higher AUAS scores.
A drug-drug interaction (DDI) study to assess the effect of oral galeterone on the pharmacokinetics (PK) of oral midazolam.
Authors: Ferrante Karen J. , Jacoby Douglas B , Sonnichsen Daryl
Published: February 2017

316

Background: Galeterone (gal) is a semisynthetic steroid that targets androgen receptor (AR) signaling via increased AR protein degradation, inhibition of CYP17 activity, and inhibition of androgen binding to AR. Gal is a novel potential treatment for prostate cancer. In vitro, gal competitively inhibits CYP3A4 (IC50 = 5.5 μM; midazolam as substrate). This clinical study evaluated whether multiple daily doses of gal alter the single-dose PK of midazolam, a sensitive probe substrate for functional CYP3A4 intestinal and hepatic activity. Methods: In an open-label, fixed sequence, DDI study, 18 healthy male volunteers received midazolam 2 mg Day 1 and Day 5 and gal 2550 mg Days 2-5. Midazolam plasma PK was determined on Days 1 and 5. The effect of gal on the natural log-transformed Cmax, AUC0-inf, and AUC0-t of midazolam was assessed with a linear mixed-effects model; point estimates for geometric means, geometric mean ratios with 90% confidence intervals were determined. Safety was also monitored. Results: The Tmax of midazolam was not altered by gal coadministration. The < 2-fold increases in midazolam Cmax and AUCs were statistically significant. For Cmax, the point estimate of the geometric least squares (LS) mean ratio between the 2 treatments was 1.25 (90% CI: 1.05, 1.48). Higher ratios were observed for the AUC ratios, with LS mean ratio for AUC0-t of 1.57 (90% CI: 1.43, 1.73) and for AUC0-inf of 1.58 (90% CI: 1.42, 1.75). The mean midazolam t1/2 was approximately 76% higher with gal coadministration. Multiple doses of gal were well tolerated with no apparent effect on the safety of midazolam. Conclusions: Per FDA guidance, < 2-fold increases in midazolam Cmax and AUCs observed with gal coadministration support its classification as a weak inhibitor of CYP3A4. Given the similar or higher in vitro IC50’s for CYP2C8 and CYP2C19, respectively, a comparable or lesser degree of enzyme inhibition is expected for gal 2550 mg daily. Based on these results, concurrent CYP3A4, CYP2C8, and CYP2C19 substrates are not contraindicated in patients taking gal; caution is advised in patients receiving or initiating sensitive CYP3A4, CYP2C8, and CYP2C19 substrates, especially those with a narrow therapeutic range.
Application of abiraterone acetate (AA) in chemo-naïve metastatic castration-resistant prostate cancer (mCRPC) patients who did not fulfil the patient inclusion criteria in the COU-AA-302 study.
Authors: Poon Darren M. C. , Kuen Chan , Lee S.H. , Chan T.W. , Sze Chun-Kin , Lee Ka Chai , Lam Daisy , Ting Chan Fong
Published: February 2017

317

Background: Visceral metastases or poor performance status (ECOG 2 or above) were the major exclusion criteria in the COU-AA-302 study, and hence the efficacy of abiraterone acetate (AA) in chemo-naïve mCRPC patients with these characteristics remain undetermined. Our study compares the clinical efficacy of AA in chemo-naïve mCRPC patients with or without the aforementioned characteristics. Methods: The clinical records of chemo-naïve mCRPC patients from all 6 public oncology centers in Hong Kong between August 2011 and December 2014 were reviewed. Patients with visceral disease who were medically unfit for, or who declined, chemotherapy, were allowed for AA in the study period. The median overall survival (OS), progression-free survival (PFS), patient and disease characteristics were compared between groups which satisfied, and did not satisfy, the inclusion criteria of COU-AA-302 study. Results: Fifty-eight consecutive chemo-naïve mCRPC patients had received AA in the review period, of which 29 fulfilled the inclusion criteria for the COU-AA-302 study (Group Eligible). All the remaining patients (Group Ineligible) had ECOG 2 or above, including 3 who had non-nodal visceral metastases. Group Ineligible had higher baseline PSA, haemoglobin and alkaline phosphatase level than Group Eligible, but otherwise there was no significant difference in the baseline characteristics between the groups for age, Gleason score, and co-morbidities. Group Ineligible had significantly shorter OS than Group Eligible (7.7 vs 25.0 months, p = 0.0095) and also a shorter PFS that did not reach statistical significance (5.3 vs 9.8 months, p = 0.2936). The duration of use of AA, and frequency of employment of post-AA treatment were comparable between the groups. Conclusions: Our study demonstrated a poor efficacy of AA in chemo-naïve patients who did not fulfil the inclusion criteria for COU-AA-302 study, by virtue of poor performance status or presence of visceral metastases. The impact of AA in this group of patients warrants further examination in clinical trials before its routine clinical use in this subgroup.
Changing characteristics of patients treated with sipuleucel-T (sip-T) over time: Real-world experience from the PROCEED registry.
Authors: Armstrong Andrew J. , Higano Celestia S. , Sartor A. Oliver , Vogelzang Nicholas J. , Berry William R. , Penson David F. , Kassabian Vahan , Nordquist Luke T. , Chang Nancy N. , LIll Jennifer Susan , Cooperberg Matthew R.
Published: February 2017

320

Background: Sip-T is an autologous cellular immunotherapy approved by the FDA for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. PROCEED (NCT01306890) is a phase 4 registry evaluating men receiving sip-T therapy in the US. Patient characteristics and treatment trends were assessed from 2011 to 2013, when several agents with an overall survival benefit became commercially available. Methods: For patients enrolled from 2011 to 2013, baseline patient and disease characteristics at the first sip-T infusion, trends in prior therapy, and pre–sip-T baseline prostate-specific antigen (PSA) levels were examined year over year. Results: From 2011 to 2013, 1902 patients were enrolled and received ≥ 1 sip-T infusion: 2011, n = 145; 2012, n = 967; 2013, n = 790. During this time period, enrollment of African American men nearly doubled from 6.9% to 13.4%, and central venous catheter use to facilitate sip-T infusion decreased (from 53.8% to 44.1%). Median baseline lactate dehydrogenase (LDH) levels and the number of lymph node metastases also decreased as well as median baseline PSA values (17.8 ng/mL to 11.9 ng/mL [P = 0.002]). Prior use of first-generation anti-androgens (from 73.1% to 60.5%), ketoconazole (17.2% vs. 6.3%), and estrogen (4.8% vs. 1.6%) decreased along with prior docetaxel use (19.3% vs. 7.5%). In contrast, prior investigational use of abiraterone acetate (from 3.4% to 8.9%) and enzalutamide (1.4% vs. 3.2%) increased over time. Conclusions: Over the duration of PROCEED, the decrease in baseline PSA, lower LDH, fewer nodal metastases, and decline in prior docetaxel use suggest that sip-T is being used earlier in the course of metastatic castration-resistant disease. Moreover, second-line hormonal therapy use with agents that do not improve overall survival appears to be substituted by therapies that do. This decrease in second-line hormonal therapies during PROCEED could suggest a real-world preference for earlier sip-T use. Clinical trial information: NCT01306890.
Simulation in oncologic care: Advancing evidence-based decisions in the management of metastatic castration resistant prostate cancer.
Authors: Herrmann Tara , Warters Martin , Blevins Douglas
Published: February 2017

322

Background: A considerable proportion of prostate cancer cases among men progress to mCRPC. As a result, appropriate treatment selection and sequencing is crucial to maximizing patient outcomes. A study was conducted to determine if simulation-based educational interventions to address underlying clinical practice gaps could improve clinical decisions of oncologists in the management of mCRPC. Methods: A cohort of US-practicing oncologists who participated in online simulation-based education was evaluated. The intervention consisted of two cases presented in a platform that allowed learners to assess the patient and choose from an extensive database of diagnostic and treatment possibilities matching the scope and depth of actual practice. Clinical decisions made by participants were analyzed using a decision engine, and instantaneous clinical guidance employing current evidence-based and expert faculty recommendations was provided at each decision point. Participant decisions before and after clinical guidance were compared using a 2-tailed paired T-test to provide p-values for assessing the impact of simulation-based education on the clinical decisions made by participants between 2/25/2014 and 9/12/2014. Results: The assessment sample consisted of 107 oncologists who made clinical decisions within the simulation. As a result of clinical guidance, significant improvements were observed in: a) Selection of an evidence-based regimen that included mCRPC targeted therapy (17%, p = 0.027) and treatment for bone metastases (26%, p < 0.0001), in an individual with a 6-year history of prostate cancer whose disease presented with bone metastasis; and b) Starting a bone resorption inhibitor (25%, p < 0.001) and switching mCRPC therapies (28%, p < 0.001) in a patient whose PSA levels were rising despite treatment. Conclusions: This study showed improvements in clinical decisions of oncologists in selecting evidence-based therapeutic regimens for patients with mCRPC. This study demonstrates that online, simulation-based instruction can result in an increase in appropriate clinical decisions, and may play a role in improving the quality of care and patient outcomes.
Long-term outcomes and predictive factors in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) showing abiraterone withdrawal syndrome (AWS) after docetaxel (DOC) treatment.
Authors: Caffo Orazio , Maines Francesca , Trentin Chiara , Veccia Antonello , Galligioni Enzo
Published: February 2017

324

Background: AWS has been rarely described as a possible PSA reduction, with or without radiological responses, observed after abiraterone acetate (AA) suspension due to disease progression. According to this possibility, all pts progressing under AA were usually monitored for at least 4 wks to evaluate if they developed AWS; if PSA decreased, the subsequent treatment was delayed until the occurrence of biochemical and/or radiological progression. The present study is aimed to assess long-term outcomes and predictive factors in DOC pre-treated mCRPC pts experiencing AWS. Methods: We evaluated a consecutive series of 73 pre-treated mCRPC pts, who received AA in our Hospital after DOC failure: all pts were treated with AA 1,000 mg po + prednisone 10 mg po daily; the treatment continued until progression disease (PD) which required to be confirmed by imaging. For each pt we have recorded the pre and post-AA clinical history, the treatment details and outcomes. All pts stopped AA due to progressive disease and AWS was defined by PSA reduction ≥ 25%, compared to the AA-end values, observed in the first month after AA stop. A logistic regression analysis was performed in order to assess the ability of a series of 18 selected clinical factors to predict AWS. Results: AWS was observed in 7 pts (9.5%) with a median duration of 17 wks (range 9-33). Two pts undergoing the 3-monthly radiographic restaging showed an objective response. A significant difference in terms of post-AA median OS was observed between AWS- and AWS+ pts (3.6 vs 27.9 mos; p = 0.02); this differences was confirmed by 1-month landmark analysis (4.6 vs 27.9 mos; p = 0.03). Among the factors, only the absence of pain at AA therapy baseline was able to predict the AWS: 100% of AWS+ pts were asymptomatic, compared to 64.6% of AWS- pts (p = 0.04). Conclusions: Despite AWS remains an unpredictable and rare phenomenon, it could represent a chance to delay the start of subsequent therapeutic line after AA failure. Moreover, our results seem to suggest that the occurrence of AWS may have a positive impact on the OS of mCRPC pts.
Activity of new agents (NAs) as third-line treatment in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) after a long-term disease control (LTDC) with abiraterone acetate (AA) or enzalutamide (ENZ) post docetaxel (DOC): Preliminary results from a multicenter Italian study.
Authors: Veccia Antonello , De Giorgi Ugo , Facchini Gaetano , Fratino Lucia , Gasparro Donatello , Alesini Daniele , Basso Umberto , Tucci Marcello , Ortega Cinzia , Scagliarini Sarah , Verderame Francesco , Lo Re Giovanni , Procopio Giuseppe , Sabbatini Roberto , Campadelli Enrico , Zucali Paolo Andrea , Morelli Franco , Sartori Donata , Conteduca Vincenza , Caffo Orazio
Published: February 2017

325

Background: Although the expected median progression free survival (mPFS) with AA and ENZ in DOC-pretreated pts is 6-8 mos, a quote of pts may experience a LTDC without progression of disease (PD) for more than 12 mos. Since the androgen receptor machinery remains the ultimate target of NAs in mCRPC post-DOC, some mechanisms of resistance could be common to all NAs. This may be crucial in planning their sequential use, mainly when a LTDC is observed in hormone NAs-based (HNAs) second line. The present study was aimed to assess the activity of NAs in pts who previously showed a LTDC with HNAs administered after DOC. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. For the study purpose, LTDC was defined as the absence of PD ≥ 12 mos in pts treated with second-line AA or ENZ. Results: A consecutive series of 291 mCRPC pts, median age 71 yrs (46-91), with bone (88%), nodal (53%) or visceral (18%) mets, was collected. All pts received NAs as second line after DOC: in particular 160 (55%) received AA and 32 (11%) ENZ, with 41 pts (21%) showing a LTDC (36 AA – 5 ENZ). Among LTDC pts, third line treatment was cabazitaxel (CABA) in 25 cases and one hormonal NA in the remaining (2 AA - 14 ENZ). The clinical outcomes of the third line therapy are detailed in the table. Conclusions: From this preliminary data, it appears that third line CABA could be slightly more active in pts achieving a LTDC with HNAs in second line LTDC, despite the clinical outcomes were not significantly different compared to HNAs. Analyses on larger patients populations are needed to confirm these findings. [Table: see text]