bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of prostate cancer national guidelines on brachytherapy monotherapy practice patterns.
Authors: Tseng Yolanda Diana , Paciorek Alan T , Martin Neil E , D'Amico Anthony Victor , Cooperberg Matthew R. , Nguyen Paul Linh 
Published: March 2020

5024 Background: In 1999, the American Brachytherapy Society (ABS) recommended brachytherapy monotherapy (BT) be limited to low-risk prostate cancer, in part because a high-impact 1998 publication suggested that intermediate or high-risk disease had worse outcomes with BT than with external beam radiation (EBRT) or radical prostatectomy (RP). We studied temporal patterns of BT use before and after the 1999 ABS published guidelines as compared with 4 other treatment options. Methods: A retrospective analysis was performed of all men with T1c-T3cN0M0 prostate cancer treated definitively in the United States from 1990 to 2011 in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry. Logistic regression was used to estimate adjusted odds ratios (AOR) comparing BT use with other treatment groups between the 1990-1998 and 1999-2011 periods, controlling for age, disease characteristics, and clinic site type. Results: 8128 men received BT (n=1117), BT+EBRT (n=313), EBRT alone (n=596), EBRT+androgen deprivation therapy (ADT, n=613), or RP (n=5489) for modified D’Amico low (n=3506), intermediate (n=2938) or high-risk (n=1684) disease. By t-tests, BT patients were younger than either EBRT or EBRT+ADT patients (both p<0.001), older than RP patients (p<0.001), and had lower risk disease than men in any of the four treatment groups (all Cochran-Mantel-Haenszel chi-square p<0.001). BT comprised 6.1% and 16.6% of all treatments in 1990-1998 and 1999-2011, respectively (Pearson p<0.01). The odds of BT use remained increased after adjusting for potential confounders (AOR 4.50, p<0.001). Increased BT use was seen only among low (AOR 5.06, p<0.001) and intermediate-risk patients (AOR 4.59, p<0.001). Among men with low or intermediate-risk disease, BT use increased compared with EBRT (AORLOW 10.00; AORINT 12.66, both p<0.001), EBRT+ADT (AORLOW 2.90, p=0.0037; AORINT 2.15, p=0.0041) and RP (AORLOW 4.76; AORINT5.10, both p<0.001). Conclusions: Despite national guidelines to the contrary, brachytherapy monotherapy for intermediate-risk prostate cancer increased over time relative to other treatments. Further studies are needed to identify factors that contribute to this evidence-practice gap.
NCIC CTG, IND-205: A phase II study of PX-866 in patients with recurrent or metastatic castration-resistant prostate cancer (CRPC).
Authors: Hotte Sebastien J. , Eisenhauer Elizabeth A. , Joshua Anthony Michael , Kumar Vikaash , Ellard Susan , Gregg Richard William , Macfarlane Robyn Jane , Winquist Eric , Torri Vamsee , Ruether Joseph D. , Basappa Naveen S. , Kakumanu Ankineedu Saranya , North Scott A. , Kollmannsberger Christian K. , Tinker Anna , Mirchandani Deepu , Tassignon Aurelie , Hausman Diana Felice , Allan Alison L , Chi Kim N. ,   NCIC Clinical Trials Group
Published: March 2020

5042 Background: PX-866 is an irreversible, pan-isoform inhibitor of Class I PI-3K. Mutations in PIK3CA and loss of PTEN activity lead to activation of AKT signaling; alterations in these genes occur frequently in prostate cancers while activation of the PI-3K/AKT signaling pathway is implicated in prostate cancer progression and treatment resistance. Hence, novel inhibitors of the pathway such as PX-866 are of interest. Methods: In this multicenter, two-stage, phase II study, docetaxel-naïve CRPC pts received PX-866, 8mg daily on a 6-week cycle. Primary endpoint was lack of progression at 12 weeks (PCWG2 criteria). Secondary endpoints included PSA and objective response rates and change in circulating tumor cells (CTC) during treatment. If ≤5 of the first 20 pts were progression free at 12 weeks, the study would stop. Otherwise, 40 pts would be accrued and PX-866 deemed worthy of further study if ≥16 pts were progression free at 12 weeks. Results: 43 pts were accrued after the criteria to progress to stage 2 were met. Median age was 70, ECOG PS was 0/1/2 in 27/15/1 pts, 23 pts had measurable disease, 24 patients had CTC ≥5. Median number of cycles was 2 (range 1–8). Most common adverse events (AE) were diarrhea (27 pts), nausea (25), fatigue (15), vomiting (13), anorexia (15) and grade 1 hypomagnesemia (11); 7 pts discontinued because of toxicity (3 GI, 3 LFTs, 1 fatigue). Grade 3 AEs were diarrhea (5 pts), AST/ALT elevation (4), fatigue (3). 11 patients were progression free at 12 weeks. 16 of the 24 pts with measurable disease were evaluable for response; there were no objective responses but 10 pts had stable disease (2.6-13.9m). One pt had a confirmed PSA response. CTC favorable conversion (from 5 at baseline to <5) was observed in 6/24 evaluable patients (25%). Correlative studies are ongoing. Conclusions: PX-866 is well tolerated and showed modest activity in CRPC but did not meet a priori benchmarks for further development as a single agent in unselected patients. As androgen receptor inhibition promotes PI3K activity in PTEN-loss PC models, the addition of PX-866 in pts whose PSA is rising on abiraterone may reverse resistance and phase B of the study is underway to test this hypothesis clinically. Clinical trial information: NCT01331083.
A randomized phase II trial of sipuleucel-T with concurrent or sequential abiraterone acetate (AA) plus prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Small Eric Jay , Lance Raymond S. , Redfern Charles H. , Millard Frederick E. , Gardner Thomas A. , Karsh Lawrence Ivan , Dawson Nancy Ann , McCoy Candice , Stubbs Andrew , DeVries Todd , dela Rosa Corazon P. , Sheikh Nadeem A. , Shore Neal D. 
Published: March 2020

5047^ Background: Sipuleucel-T and AA + P are FDA-approved for asymptomatic/minimally symptomatic mCRPC. Suppression of the androgen axis can be immunostimulatory and AA suppresses circulating androgen levels; AA plus sipuleucel-T may therefore be synergistic. However P used with AA, which may be immunosuppressive, has not been studied with concurrent sipuleucelET and could impair sipuleucel-T production and/or immunologic response. P11-3 (NCT01487863) is the 1st study to evaluate the combination of sipuleucel-T and AA + P Methods: Patients (pts) with asymptomatic/minimally symptomatic mCRPC were randomized (1:1) to sipuleucel-T (3 infusions at approx 2-wk intervals) with up to 26 wks of AA + P (AA 1000mg QD + P 5mg BID) starting 1 day after the 1st sipuleucel-T infusion (concurrent, arm A) or at 10 wks following the 1st sipuleucel-T infusion (sequential, arm B). Endpoints included the effect of AA + P on product (sipuleucel-T) characteristics eg antigen presenting cell (APC) activation, measured as CD54 upregulation (primary endpoint), APC (measured as CD54+ cells) and total nucleated cell (TNC) counts, as well as safety and immunologic responses. Results: 31 pts in arm A and 32 pts in arm B completed sipuleucel-T treatment by the interim analysis (Nov 2012). Baseline characteristics were similar in the 2 arms. 60/63 pts received all 3 infusions of sipuleucel-T. No significant differences in median cumulative APC activation, APC count or TNC count were seen between the arms. Increased CD54 upregulation with the 2nd and 3rd treatments were indicative of a prime boost effect in both arms. Similar profiles of antigen-specific humoral and cellular immune responses were generated with no difference in magnitude of response between the arms (p>0.05). The incidence of adverse events (AEs) and serious AEs was similar in both arms. Conclusions: These data suggest sipuleucel-T can be successfully manufactured during concurrent AA + P. Product potency and prime boost effect were similar to sipuleucel-T alone. Immune responses and AEs were similar in both arms. It is not known if sipuleucel-T will provide similar efficacy with concurrent or sequential AA + P. Clinical trial information: NCT01487863.
Detecting lower in addition to the highest Gleason score prostate cancer on core biopsy and the risk of prostate cancer-specific mortality.
Authors: Aizer Ayal A. , Phillips John , Chen Ming-Hui , Zhang Danjie , Loffredo Marian , D'Amico Anthony Victor 
Published: March 2020

5051 Background: We evaluated the risk of prostate cancer-specific mortality (PCSM) following definitive treatment in men with at least one prostate biopsy core with a Gleason score (GS) lower than the highest GS identified. This pattern termed “ComboGS” in a concurrent submission was shown to be associated with a significant reduction in the odds of upgrading at radical prostatectomy (RP). Methods: In this validation cohort 666 men with localized or locally advanced prostate cancer, men were diagnosed via a transrectal, ultrasound-guided needle prostate biopsy (median 6, IQR 5-6 cores) and treated definitively between 1989-2000 with either RP or radiation (RT) or RT and hormones (HT) at a regional radiation oncology center. Patients could be referred into this center from 6 community based hospitals in Southeastern Massachusetts and Rhode Island. Community based pathologists from these 6 health care facilities assigned the biopsy GS used for the analyses in this study. Multivariable competing risks regression was performed (Table) to assess the impact of ComboGS on the risk of PCSM adjusting for age, established PC prognostic factors, and treatment. Results: After a median follow up of 4.6 years (IQR 2.5-6.7 years), 168 men (25.2%) died, 41 (24.4%) of PC. ComboGS was associated with a decreased risk of PCSM (Adjusted Hazard Ratio (AHR) 0.40, 95% Confidence Interval (CI) 0.19-0.85, p=.017). Estimates of PCSM were significantly lower in men with versus without ComboGS when the highest GS was ≥7 (p<.001) but not 6 or less (p=.71). Specifically these 5-year estimates were 14.4% and 4.8% versus 1.9% and 2.7% respectively. Conclusions: In addition to lower odds of upgrading at RP, using an independent data set the ComboGS assessed by community based pathologists serving 6 hospitals was found to also be associated with a decreased risk of PCSM. [Table: see text]
Open-label, multicenter study of sipuleucel-T in men with metastatic castrate-resistant prostate cancer (mCRPC) previously treated with sipuleucel-T: Evaluation of antigen presenting cell (APC) activation and ELISPOT data.
Authors: Beer Tomasz M. , Glode L. Michael , Lance Raymond S. , Greengold Richard H. , dela Rosa Corazon P. , Sims Robert Brownell , Wang Yang , Sheikh Nadeem A. , Corman John M. 
Published: March 2020

5053^ Background: P10-1 (NCT01338012) is a study of sipuleucel-T, an autologous cellular immunotherapy, in men with mCRPC previously treated with sipuleucel-T in PROTECT (NCT00779402). This preliminary analysis of P10-1 evaluates APC activation (a measure of product potency) and immune responses in men retreated with sipuleucelET. Methods: Men who received ≥1 infusion of sipuleucel-T in PROTECT and progressed to mCRPC were retreated with 3 infusions of sipuleucel-T. APC activation was assessed by CD54 upregulation. T cell responses to prostatic acid phosphatase (PAP) and PA2024 (PAP-GM-CSF) antigens were assessed by IFN-γELISPOT assay. Results: As of October 23, 2012, 7 men were enrolled and received ≥1 infusion. Median time between the third PROTECT infusion and first P10-1 infusion was 9.2 (range: 7.8–10.0) years. APC activation was greater at the first P10-1 treatment vs the last PROTECT treatment (Table). PA2024 and PAP ELISPOT responses were present prior to retreatment, indicating long-term memory (Table 1); based on other studies of sipuleucel-T, ELISPOT responses are not generally present prior to the first treatment (Beer. Clin Cancer Res 2011; Sheikh. Cancer Immunol Immunother 2013). Conclusions: This is the first trial to report the feasibility of sipuleucel-T retreatment following treatment in an earlier stage of prostate cancer. These data indicate the presence of existing immunological memory to the immunizing antigen several years after initial treatment. In addition, retreatment with sipuleucel-T appeared to boost product potency compared with prior treatment. Clinical trial information: NCT01338012. [Table: see text]
Interim safety analysis of a compassionate-use program (CUP) and early-access program (EAP) providing cabazitaxel (Cbz) plus prednisone (P) to patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel.
Authors: Malik Zafar I. , Di Lorenzo Giuseppe , Basaran Mert , Ardavanis Alexandros , Parente Phillip , de Schultz Wito , Saad Fred , van Oort Inge , Gerritsen Winald R. , Antón Aparicio Luis M. , Matus Geoffrey , Hitier Simon , Heidenreich Axel , Bahl Amit 
Published: March 2020

5055 Background: Cbz + P provides a significant survival benefit vs mitoxantrone + P in pts with mCRPC (Phase III TROPIC study [NCT00417079]; hazard ratio 0.70; p < 0.0001). These findings supported the initiation of ongoing Sanofi-funded CUP and EAP (NCT01254279) to provide access to Cbz prior to commercialization and to collect real-life safety data. Methods: Expected enrollment is ~1600 pts with mCRPC from 250 centers worldwide. Pts receive Cbz (25 mg/m2 Q3W) + P (10 mg oral QD) until progressive disease (PD), death, unacceptable toxicity, physician/pt decision or Cbz commercial availability. Pts are followed until 30 days after last dose. Granulocyte colony-stimulating factor (G-CSF) use is recommended as per ASCO guidance. Results: Interim baseline and safety data from the first 1301 pts treated in 37 countries are now available. Mean age was 68 yrs (22% were ≥ 75 yrs). All pts had an ECOG performance status ≤ 2. Median time from initial prostate cancer diagnosis was 57.6 months and 60% of pts had ≥ 2 metastatic sites; the most common were bone (91%) and lymph nodes (regional 30%, distant 27%). In total, 17% had PD whilst on docetaxel. The median number of Cbz cycles was 6 (range 1–22); median relative dose intensity was 99%. Overall, 837 pts (64%) received G-CSF (n = 123 curative [C], n = 765 prophylactic [P] and n = 99 [C + P]). Of 1142 pts (88%) who discontinued Cbz + P, the most common reasons were PD (44%), adverse event (AE; 27%), physician decision (13%) and commercial availability of Cbz (7%). Grade 3–4 AEs possibly related to Cbz + P occurred in 43% of pts; the most frequent were clinical neutropenia (18%), febrile neutropenia (FN; 7%) and diarrhea (4%). Of 80 pts (6%) with AEs leading to death, the AE was related to Cbz + P in 39 pts (3%). Conclusions: These results provide valuable data on Cbz + P treatment in routine clinical practice, confirming the safety results of clinical trials and showing that treatment with Cbz + P is associated with a manageable safety profile. The incidence of FN seems slightly lower than in TROPIC, owing to more frequent use of G-CSF prophylaxis in the CUP and EAP. Clinical trial information: NCT01254279.
Use of serum markers in prediction of survival in the trapeze factorial trial evaluating docetaxel with zoledronic acid, strontium-89, or both in castrate-refractory prostate cancer (CRPC) metastatic to bone.
Authors: Wadhwa Vivek K , Pirrie Sarah , Wen Kai Sheng , Barton Darren , James Nicholas David 
Published: March 2020

5057 Background: There is emerging interest in the use of bone turnover markers in CRPC to compliment current modalities and aid therapeutic management decisions. We report the preliminary results of investigation into the clinical utility of P1NP, total alkaline phosphatase (ALP) and PSA as parameters of survival in a representative sample of patients from TRAPEZE. Methods: Baseline and post treatment (cycle six or end of treatment if sooner) samples were taken from 120 patients equally distributed across the trial arms of TRAPEZE. Absolute and percentage change in the markers were investigated in relation to overall survival (OS) using the Cox Regression model. Results: Of the 120 patients, 38(32%) failed to complete 6 cycles. No relationship was observed between P1NP and OS using either absolute or percentage change (p=0.59, p=0.64). Absolute change in log PSA was significantly related to OS (HR=1.22 (95%CI 1.01, 1.48), p<0.05, respectively) however percentage change in log PSA did not reach statistical significance (HR=1.006 (95%CI 0.99, 1.01), p=0.095). Absolute change in ALP was found to be inversely related to OS (HR=0.999 (95%CI 0.998, 0.999), p<0.001) but percentage change in ALP was not significant (p=0.89). When the PSA and ALP models were applied to the entire trial set (757 patients) the predictive value of both absolute and percentage change in log PSA remained highly significant (HR=1.23, p<0.001 & HR=1.01, p<0.001). In addition the significance of absolute change in ALP also remained (HR=0.999, p<0.05). Conclusions: Changes in P1NP were not related to OS in CRPC patients metastatic to bone. Absolute change in ALP was inversely related to OS and both absolute and percentage changes in log PSA were also related to OS in this sub-study. When applied to the entire TRAPEZE patient group all remained statistically significant. The utility of changes in ALP and PSA, as prospective markers for studies in CRPC patients metastatic to bone, merit further evaluation.
Efficacy of docetaxel chemotherapy in metastatic prostate cancer (mPC) patients (pts) experiencing early castration resistance (CR).
Authors: Huillard Olivier , Albiges Laurence , Eymard Jean-Christophe , Massard Christophe , Di Palma Mario , Escudier Bernard J. , Fizazi Karim , Loriot Yohann 
Published: March 2020

5075 Background: mPC pts experiencing a short period of sensitivity to initial androgen deprivation therapy (ADT) have an unfavourable prognosis and lower probability of response to 2nd-line endocrine therapy suggestive of androgen receptor (AR) pathway-independent mechanisms of resistance. Recent studies have shown that docetaxel may kill PC cells through AR targeting. We thus investigated whether docetaxel may have efficacy in pts with early CR. Methods: Two independent prospective databases (Institut Gustave Roussy and Institut Jean Godinot) of mCRPC pts were analyzed. Early CR was defined as progression within the first year of ADT. The primary endpoint was time to progression (TTP) on docetaxel. Secondary criteria were clinical benefit (decrease in 2 points on a 0-to-10-pain-scale or in dose or type of pain medication), PSA response (decrease > 50% in PSA serum level) and overall survival (OS). Pts with early CR were compared to pts with sensitivity to initial ADT > 1 year (t-test for quantitative data, χ-2 test or Fischer’s exact test for qualitative data, Logrank test for TTP and OS). Results: 188 pts were selected for analysis. A higher frequency of unfavourable prognostic factors in pts with early CR as compared with others pts was observed with a median PSA serum level of 81 ng/dl (4-8000) vs 35 ng/dl (4-4260) (p=5.10-5), presence of visceral metastasis in 11% vs 2% of pts (p=0.01) and Gleason score ≥ 8 in 63% vs 41% of pts respectively (p=0.001). Clinical benefit and PSA response on docetaxel were observed in 84% vs 89% of pts (p=0.45) and 67% vs 81% of pts (p=0.10) respectively. Median TTP was 6.1 months (95%CI=6-7.5) vs 7.8 months (95%CI=7-8.3) (p=0.04). Median OS was 22.4 months (95%CI=17.1–28.6) vs 36.1 months (95%CI=26.3–42.4) (p=0.002). Conclusions: mPC pts experiencing early CR have more unfavourable baseline prognostic factors, shorter TTP on docetaxel and shorter OS as compared with pts experiencing time to CR > 1 year. However, similar clinical and biological benefits from docetaxel chemotherapy were observed in this subset of pts. Since they have lower probability of response to second-line endocrine therapy, docetaxel appears as the best option after progression on initial ADT.
Array CGH and DNA sequencing to personalize targeted treatment of metastatic breast cancer (MBC) patients (pts): A prospective multicentric trial (SAFIR01).
Authors: Andre Fabrice , Bachelot Thomas Denis , Campone Mario , Arnedos Monica , Dieras Veronique , Lacroix-Triki Magali , Lazar Vladimir , Gentien David , Cohen Pascale , Goncalves Anthony , Lacroix Ludovic , Chaffanet Max , Dalenc Florence , Mathieu Marie-Christine , Bieche Ivan , Olschwang Sylviane , Wang Qing , Commo Frederic , Jimenez Marta , Bonnefoi Herve R. 
Published: March 2020

511 Background: The aim of the present study was to profile the metastatic lesion of pts using high throughput technologies, and to treat them accordingly. Methods: SAFIR01 trial aimed to include 400 pts with MBC, selected for not presenting a progressive disease at the time of biopsy. A biopsy was done in a metastatic site. DNA was extracted if the tumor contained >50% cancer cells, and sent to one of the 5 genomic centers who performed array CGH (copy number changes) and sanger sequencing on PIK3CA (exon 10/21) and AKT1 (exon 3). A targeted therapy matched to the genomic alteration was expected to be proposed at the time of progressive disease. The primary endpoint was the % of pts who received a targeted therapy according to the genomic alteration. Results: A biopsy of metastatic site was done successfully in 408 out of the 423 included pts. Biopsy was complicated by a serious adverse event in 9 pts. A discrepancy between primary and metastatic lesion was observed in 8% and 19% of pts for Her2 and HR. Array CGH and sequencing were successfully obtained in 277 (68%) and 295 (72%) pts. The main reason for failure of genomic test was the low cellularity (n=93). A targetable genomic alteration was identified in 204 pts. The most frequent genomic alterations were PIK3CA mutations, CCND1, FGF4 and FGFR1 amplifications. 76 pts presented a rare targetable genomic alteration (<5%), including AKT1 mutations, EGFR, FGFR2, PIK3CA, MDM2 amplifications. Early Feb 2013, 4 6 out of 277 pts with genomic analyses (17%) had received a targeted therapy matched to the genomic alteration, covering twelve different targets. Updated results on number of pts treated, together with efficacy data will be presented. Next generation sequencing on metastatic lesions is ongoing and results will be presented. Conclusions: This trial evaluated the concept of personalized medicine for MBC and provided a large scale genomic analysis of metastatic tissue. This study suggests that assessing the biology of metastatic tissue could allow driving pts to targeted therapy. A randomized trial (SAFIR02) testing this approach is expected to start during summer 2013. Clinical trial information: NCT01414933.