bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baseline covariates impacting overall survival (OS) in a phase III study of men with bone metastases from castration-resistant prostate cancer.
Authors: Fizazi Karim , Massard Christophe , Smith Matthew Raymond , Rader Michael E. , Brown Janet Elizabeth , Milecki Piotr , Shore Neal D. , Oudard Stephane , Karsh Lawrence Ivan , Carducci Michael Anthony , Damião Ronaldo , Wang Huei , Goessl Carsten Dietrich 
Published: March 2020

4642 Background: Prognostic models of OS in men with metastatic castrate-resistant prostate cancer (M+CRPC), have been limited. Here we present an analysis of baseline covariates associated with OS from an international phase 3 study that demonstrated superiority of denosumab over zoledronic acid for prevention of skeletal-related events (SRE) in this population (Fizazi et al., Lancet 2011;377:813-822). Methods: Patients had confirmed bone metastases (BM) from CRPC (a rising PSA despite castrate testosterone levels) and no prior bone anti-resorptive therapy. Proportional hazards modeling with various selection strategies was used to assess the prognostic significance of baseline covariates in multivariate analyses. Study-specified factors (previous SRE [Y vs N], PSA level [<10 vs ≥10 ng /mL]) and additional variables (Cook et al., Clin Cancer Res 2006;12:3361-3367; Halabi et al., J Clin Oncol 2003;21:1232-1237; Halabi et al., J Clin Oncol 2008;26:2544-2549) were explored. As no difference in OS was observed between treatment arms, analyses were performed using the pooled overall patient population. Results: Analyses included all randomized subjects with available baseline covariate data (n=1745). At the primary analysis date (median study duration 12.2 months), OS was 51%. Various selection strategies produced consistent results. In multivariate analysis, bone-specific alkaline phosphatase (BAP) ≥146 μg/L (p<0.0001) and corrected urinary N-telopeptide (uNTx) >50 nmol/mmol (p=0.0008) were associated with shorter OS, as were prior SRE (p=0.0002), PSA ≥10 ng /mL (p<0.0001), visceral metastases (p=0.0002), greater time from either diagnosis to first BM or first BM to randomization (p<0.0001 for both), ECOG performance status 2 vs. 0/1 (p=0.017), BPI-SF pain score >4 (p<0.0001), age (p=0.008), alkaline phosphatase >143 U/L (p<0.0001), and hemoglobin ≤128 g/L (p<0.0001). Conclusions: Besides known factors previously associated with OS in men with CRPC (Halabi et al., 2003), we show that bone-associated covariates (pain, prior SRE, BAP, and uNTx) are also important and independent prognostic factors for OS.
Correlation of increased eosinophil count following sipuleucel-T treatment with outcome in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: McNeel Douglas G. , Lin Daniel W. , Gardner Thomas , Sheikh Nadeem A. , Whitmore James Boyd , Sims Robert Brownell , Dreicer Robert 
Published: March 2020

4650 Background: Sipuleucel-T is the first autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic mCRPC. In the IMPACT trial, pts treated with sipuleucel-T had transient increases in eosinophil counts compared with control. In this retrospective analysis, we assess potential correlations between eosinophilia, overall survival (OS), prostate cancer-specific survival (PCSS) and immune response following sipuleucel-T. Methods: Data from three phase III trials (D9901, D9902A, and IMPACT) were pooled. The analysis included CBCs performed at baseline and wks 2–34. Eosinophilia was defined as either >ULN (with normal baseline), or a max change from baseline within the top quartile, at any time between wks 2–16. Results: Increased eosinophil counts were seen in sipuleucel-T pts by wk 6, decreasing to near baseline by wk 14; eosinophil counts in control pts were stable. Of 377 sipuleucel-T pts eligible for analysis, 105 (27.9%) had eosinophilia. Baseline disease characteristics associated with eosinophilia were indicative of better prognosis (i.e., longer Halabi predicted survival [p=0.007], lower PSA [P=0.033], higher Hgb [p<0.001], and no prior docetaxel [p=0.012]). In univariate analyses, eosinophilia correlated with improved OS (HR=0.75; 95%CI: 0.56–1.01; p=0.057) and PCSS (HR=0.71; 95%CI: 0.53–0.97; p=0.031); trends persisted after adjusting for Halabi. The magnitude of eosinophilia positively correlated with antigen-specific humoral responses (p ≤0.039 for wks 6, 14 and 26) and elevations in the cytokines at wk 6 (IL2 [p=0.011], IL5 [p=0.038] and TARC [p=0.001]). AEs occurring more frequently (p<0.05) in pts with eosinophilia were infusion-related: pyrexia (33.3 v 21.3%) and nausea (19.0 v 10.7%). No cases of hypereosinophilic syndrome were reported. Conclusions: Increases in eosinophils after sipuleucel-T correlated with improved OS and PCSS. Large increases in eosinophil counts were associated with humoral responses and Th2-type cytokine production. Further studies of eosinophilia as a biomarker for sipuleucel-T response, particularly in earlier disease settings, are of interest.
Comparing the ability of clinicians and a nomogram model at predicting future 99mTc-bone scan (BS) positivity in patients (pts) with rising prostate-specific antigen (PSA) following radical prostatectomy (RP) for prostate cancer (PCa).
Authors: Kattan Michael W. , Yu Changhong , Stephenson Andrew J. , Sartor A. Oliver , Tombal Bertrand 
Published: March 2020

4652 Background: Nomograms that assist clinicians in predicting which PCa pts have a high risk of developing M1 disease have been developed, but clinicians still tend to use their own judgment of risk when managing individual pts. This is the first study to compare the ability of clinicians vs a nomogram at predicting future BS positivity in pts with PCa. Only androgen deprivation therapy- (ADT-) naive post-RP pts were considered, as there are currently no nomograms for predicting M1 disease in pts receiving ADT. The Slovin nomogram (Slovin et al. Clin Cancer Res 2005; 11: 8669-8673) was chosen based on considerations of the numbers of pts analyzed and the follow-up intervals used in its development. Methods: During an advisory board in June 2011, 24 PCa experts were given details of 25 ADT-naive post-RP PCa pts with biochemical recurrence who were randomly selected from the Cleveland Clinic Database of 759 pts. The predicted 1-yr from today probability of freedom from metastasis was generated using the Slovin nomogram and estimated by the clinicians. The predictive accuracy was quantified using the concordance index (C-index). Results: All pts were Caucasian and median age was 62 yrs. Median PSA level at biochemical recurrence was 1.2 ng/mL and PSADT varied between 1.3 and 11.7 months. The data used for each of the pts was acquired between 4 and 133 months after the RP procedure. Eight pts had a positive BS within 1 yr. Considerable variation between the clinicians’ predictions for each pt was observed. The nomogram gave a higher C-index compared to the clinicians (0.812 and 0.628, respectively; p=0.003). The clinicians typically overestimated the risk of developing M1 disease. The nomogram outperformed all of the clinicians (C-index range: 0.47 to 0.75). Urologists predictions were superior to those of oncologists (p=0.048). Conclusions: The Slovin nomogram was more accurate than expert clinicians in predicting 1-yr BS positivity. We suggest nomograms should become an integral part of the clinical decision process in the PCa setting.
A phase II study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer (CRPC): A PCCTC trial.
Authors: Antonarakis Emmanuel S. , Heath Elisabeth I. , Posadas Edwin M. , Harrison Michael Roger , Bruce Justine Yang , Yu Evan Y. , Cho Steve Y. , Wilding Gregory E. , Fetterly Gerald J. , Hangauer David G. , Kwan Min-Fun Rudolf , Dyster Lyn M. , Carducci Michael Anthony ,   Prostate Cancer Clinical Trials Consortium (PCCTC)
Published: March 2020

4654 Background: KX2-391 is an oral small molecule inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, PSA declines were seen in men with advanced prostate cancer. Methods: A single-arm phase 2 study of KX2-391 in 31 men with chemo-naïve bone-metastatic CRPC was conducted at 5 PCCTC sites. Men received oral KX2-391 (40 mg BID) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) at 24 wk (progression = clinical/radiographic progression or death, but not rising PSA; PCWG2 criteria); a 50% success rate was predefined as clinically significant. Secondary endpoints were PSA progression-free survival (PPFS) at 24 wk (PSA progression = 25% PSA rise above nadir; PCWG2 criteria); median PFS; median PPFS; and max PSA decline. Exploratory outcomes included PK studies, CTC enumeration, and analysis of markers of bone resorption (urinary N-telopeptide [uNTx]; C-telopeptide [CTx]) and formation (bone alk phos [BAP]; osteocalcin). Results: The trial closed early after accrual of 31 men, due to a prespecified futility rule. In all, 26/31 men were evaluable for the primary endpoint; efficacy results are shown below. Also, 2/11 men (18%) with unfavorable (≥5) CTCs at baseline converted to favorable (<5) CTC counts on study, and 18/19 men (95%) with baseline favorable CTC counts maintained them. The proportion of men with declines in bone turnover markers was 32% (8/25) for uNTx, 21% (6/29) for CTx, 10% (3/29) for BAP, and 25% (7/28) for osteocalcin. In PK studies, median Cmax was 61 (range 16–129) ng/mL, and AUC was 156 (35–348) ng*hr/mL. Common toxicities (≥10%) included LFT elevations, leukopenia, thrombocytopenia, fatigue, nausea and constipation. Conclusions: KX2-391 dosed at 40 mg BID lacks antitumor activity in men with CRPC, but modulates bone turnover markers in some men. Because a Cmax of >142 ng/mL is required for tubulin polymerization inhibition, higher once-daily dosing will be used in future trials. [Table: see text]
Results of telomerase activity measurements from live circulating tumor cells captured on a slot microfilter in a phase III SWOG-coordinated prostate cancer trial (S0421).
Authors: Goldkorn Amir , Ely Benjamin , Quinn David I. , Tangen Catherine M. , Tai Yu-Chong , Twardowski Przemyslaw , Van Veldhuizen Peter J. , Agarwal Neeraj , Carducci Michael Anthony , Monk J. P. , Garzotto Mark , Mack Philip C. , Lara Primo , Higano Celestia S. , Hussain Maha , Vogelzang Nicholas J. , Cote Richard J , Thompson Ian Murchie ,   Southwest Oncology Group
Published: March 2020

4663 Background: Analysis of circulating tumor cells (CTC) is a promising biomarker strategy in advanced prostate cancer, and telomerase activity (TA) is a recognized cancer marker. To test whether CTC TA is prognostic for survival (OS), we developed a novel Parylene-C slot microfilter capable of capturing live CTC and used it to measure CTC TA as part of a Phase III SWOG-coordinated therapeutic trial in metastatic castration resistant prostate cancer (S0421). Methods: Blood samples were drawn into EDTA tubes and shipped overnight to a central processing site. After Ficoll centrifugation, low constant pressure was used to pass the mononuclear cell layer through two slot microfilters in series as published previously (filter1 captures CTC + background white blood cells; filter2 captures only background white blood cells). Filter-trapped cells were lysed in CHAPS buffer and assayed for TA using qPCR-based telomeric repeat amplification. In parallel, CTC were enumerated using CellSearch (J&J). Cox regression was used to evaluate the association between baseline (pre-treatment) TA and OS overall, and within subgroups characterized by good prognosis (<5) vs. poor prognosis (>=5) baseline CTC counts. CART regression was used to explore potential prognostic subgroups based on baseline PSA, CTC, and TA cutpoints. Results: Samples were obtained from 263 patients. While no association was observed between TA and OS overall, in patients with baseline CTC >=5 (108 of 263 or 41% of patients), TAfilter2 – TAfilter1 representing high CTC TA relative to background blood cells was associated with a hazard ratio (HR) of 1.14 (95% CI 1.05-1.23, p<0.001) for OS after adjusting for risk factors and remained significant when also adjusting for CTC: HR 1.14 (95% CI 1.04-1.23; p=0.005). Exploratory CART regression assessing baseline PSA, CTC, and TA identified risk groups based only on CTC and TA values. Conclusions: Baseline TA from CTC live-captured on a new slot microfilter is the first CTC biomarker shown to be prognostic of OS in men with CTC counts >=5 in a prospective clinical trial. CTC TA may be useful for further identifying prognostic groups in this population.
Long-term follow-up of a randomized trial comparing conventional paclitaxel and carboplatin with dose-dense weekly paclitaxel and carboplatin in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: JGOG 3016 trial.
Authors: Katsumata Noriyuki , Yasuda Makoto , Isonishi Seiji , Michimae Hirofumi , Kimura Eizo , Aoki Daisuke , Jobo Toshiko , Kodama Shoji , Terauchi Fumitoshi , Tsuda Hiroshi , Sugiyama Toru , Ochiai Kazunori ,   Japanese Gynecologic Oncology Group
Published: March 2020

5003 Background: The primary analysis of the JGOG3016 trial (Lancet 2009, 374:1331) showed that dose-dense weekly administration with paclitaxel and carboplatin (dd-TC) demonstrated statistically significant efficiency over tri-weekly administration withTC (c-TC) as first-line chemotherapy in patients with stage II-IV epithelial ovarian, fallopian tube or primary peritoneal cancer. We report the long-term follow-up results on progression-free survival (PFS) and overall survival (OS). Methods: Patients with stage II to IV ovarian cancer were randomly assigned to receive c-TC (carboplatin AUC 6 and paclitaxel 180 mg/m2 on day 1) or dd-TC (carboplatin AUC 6 on day 1 and paclitaxel 80 mg/m2 on day 1, 8, 15). The treatments were repeated every 3 weeks for six cycles; in responding patients, additional three cycles were administered. Results: The analysis included eligible 631 patients. At 6.4 years of median follow-up, there continues to be a highly statistically significant improvement in median PFS in favor of the dd-TC group compared with the c-TC group (28.1 vs. 17.5 months, hazard ratio [HR] 0.75, 95% CI, 0.62-0.91; P=0.0037). Median survival has not yet been reached in the dd-TC group, and OS at 5 years was higher in the dd-TC group than the c-TC group (58.6% vs. 51.0%, HR 0.79, 95% CI, 0.63-0.99; P =0.0448). Conclusions: The dd-TC improves long-term PFS and OS in patients with advanced epithelial ovarian cancer.
Impact of metformin use on risk of recurrence in high-grade endometrial cancers.
Authors: Ko Emily Meichun , Franasiak Jason , Clark Leslie Horn , Gehrig Paola A. , Bae-Jump Victoria Lin 
Published: March 2020

5009 Background: Obesity and diabetes (DM) have been linked to increased recurrence rates and worse survival in endometrial cancer. Metformin is widely used as the first line treatment for type II DM. Recent epidemiological evidence suggests that metformin may lower cancer risk and reduce cancer-related deaths among DM patients. However, no studies have assessed the effect of metformin use on endometrial cancer outcomes. Methods: A retrospective cohort analysis was conducted of all grade 3 endometrial cancer patients with DM at a single institution from 2005-2010. Clinical-pathologic data was abstracted, including metformin, insulin, sulfonamide and thiazolidinedione use at the time of cancer diagnosis. Statistical analysis were performed using summary statistics and multivariate cox analysis, with two tailed p-values <0.05 considered significant. Results: 55/329 patients with grade 3 cancer had DM. Mean age was 68.3 (sd 8.4), and BMI 35.7 (sd 9.4). Stage distribution consisted of 58.2% stage I, 7.3% stage II, 27.3% stage III, and 7.3% stage IV. Histology included 41.8% endometrioid, and 58.2% serous or clear cell. 56.4% of diabetics used metformin and 43.6% did not. Mean follow-up was 21.6 months (sd 15.0). After adjusting for BMI, myometrial invasion, stage, histology, adjuvant treatment, and non-metformin DM medications, metformin use was significantly associated with decreased cancer recurrence (HR 0.06, 95CI 0.01, 0.40; p<0.004). Conclusions: Metformin use was associated with a decreased risk of recurrence in high-grade endometrial cancer, suggesting that it may have a role as adjuvant and maintenance therapy for this obesity-driven disease. [Table: see text]
Adjuvant therapy with zoledronic acid (AZURE-BIG 01/04): The influence of menopausal status and age on treatment effects.
Authors: Marshall Helen , Gregory Walter , Bell Richard , Cameron David A. , Dodwell David John , Keane Maccon M. , Gil Gil Miguel J. , Davies Claire , Coleman Robert Edward ,   AZURE Investigators
Published: March 2020

502 Background: The AZURE trial evaluated the use of zoledronic acid (ZOL) in addition to standard adjuvant therapy in patients with stage II/III breast cancer. Although analysis of the primary endpoint in the total study population showed no significant effects on disease outcomes, pre-specified subgroup analyses identified significant benefit in both invasive disease-free survival (IDFS) and overall survival (OS) in women >5years postmenopause (Coleman et al. NESM. 2011;365:1396–1405). Here we evaluate the treatment modifying effects of both menopausal status and age. Methods: 3360 patients were randomized to receive standard (neo) adjuvant systemic therapy +/- ZOL 4mg iv every 3-4 weeks for 6 doses, then at reduced frequency to complete 5 years treatment. Results: ZOL had no overall effect on IDFS or OS at a median follow-up of 59 months. Pre-specified subgroup analyses showed significant heterogeneity of treatment effect (chi21 =7.91; p=.0049) on IDFS between those who were >5 years post-menopause (n=1041; adjusted HR= 0.75; 95% CI 0.59-0.96, p=0.02) and all other (pre, peri and unknown status) menopausal groups (n=2318; adjusted HR= 1.15; 95% CI 0.97-1.36, p=0.11). The treatment interaction between the two menopausal groups was related to differences in first extra-skeletal IDFS events (chi21 = 14.00, p=0.0002), rather than first recurrence in bone (chi21 = 0.14, p=0.70). In women aged <40, a significant worsening in extra-skeletal IDFS events was seen (HR = 1.68; 95% CI = 1.14-2.47, p=.008). Although the ZOL effect on IDFS improved by age from a negative effect in younger patients (<40) to a beneficial effect for those aged 54 and over (chi21(trend) = 5.96, p=0.015, using Cox model analysis to test for an interaction effect between age, menopausal status and treatment for IDFS (using age 55 as a cut-off) showed that the age effect is reversed by menopausal status, with this model providing a significantly better fit (chi22 = 22.8, p=.00001) than the aforementioned linear model. Conclusions: These results suggest menopausal status is more informative than age in the selection of patients for treatment with ZOL. In women aged <40, ZOL may increase extra-skeletal recurrence.
Use of chemotherapy (CT) in BRCA1/2-deficient ovarian cancer (BDOC) patients (pts) with poly-ADP-ribose polymerase inhibitor (PARPi) resistance: A multi-institutional study.
Authors: Ang Joo Ern , Gourley Charlie , High Hilda Anne , Shapira-Frommer Ronnie , Powell C. Bethan , Castonguay Vincent , De Greve Jacques , Yap Timothy Anthony , Fong Peter C.C. , Olmos David , Banerjee Susana N. , Chen Lee-may , Friedlander Michael , Kaufman Bella , Oza Amit M. , De Bono Johann Sebastian , Gore Martin Eric , Kaye Stanley B. 
Published: March 2020

5022 Background: Emerging clinical data point to the clinical utility of PARPi in BDOC. However, the impact of PARPi exposure on the prospects of response to further CT remains unclear. In our previous single centre study, we provided the first clinical data relating to the use of post-PARPi CT (JCO 2010: 28(15S), A5041). Our aim here was to re-examine this issue in a larger multi-institutional population. Methods: We included pts with advanced BDOC who received CT, having progressed on ≥200 mg bd olaparib. Pt, tumor and treatment characteristics and clinical outcomes were documented. Relationships between post-PARPi CT overall survival (OS) and other variables were explored using Cox regression. Results: We collected data on 75 pts (median age 51 y [range 31-77], BRCA1:BRCA2 54:21, mean 3 previous lines of CT [95% CI 2.5-3.4], pre-PARPi platinum (Plt) resistance rate 49% and olaparib RECIST-response rate [RR] 39% [95% CI 28-50]). Following olaparib, most pts received Plt alone or in combination with taxane (Tx) or liposomal doxorubicin (PLD). Weekly Plt was used in 36% of all Plt-treated pts, mainly in combination with weekly Tx. Overall RECIST and CA125 (GCIG) RRs were 38% and 48%, respectively; these responses occurred independently of PARPi response or pre-PARPi Plt sensitivity (all p>.1). The median progression free survival and OS of RECIST responders were 7.9 m (95% CI 5.8-10.9) and 10.5 m (95% CI 1.4-19.6), respectively. In all pts, the median OS from the start of post-PARPi CT was 7.9 m (95% CI 5.7-10.1) while that from diagnosis was 64.9 m (95% CI 52.9-76.9). Factors associated with improved OS on post-PARPi CT in the MVA included best olaparib response of non-disease progression (p=.003, HR 0.28), optimal initial debulking (p=.01, HR 0.36) and pre-PARPi Plt sensitivity (p=.05, HR 0.46). Conclusions: These data indicate potential for meaningful responses to CT in BDOC pts with PARPi resistance. Analysis to identify molecular predictors of response is ongoing. [Table: see text]
Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabin plus carboplatin (GC) or carboplatin plus pegylated doxorubicin (PLDC): A randomized phase III trial of the NOGGO-AGO-Germany-AGO Austria and GEICO-GCIG intergroup study (HECTOR).
Authors: Sehouli Jalid , Meier Werner , Wimberger Pauline , Chekerov Radoslav , Belau Antje , Mahner Sven , Kurzeder Christian , Hilpert Felix , Klare Peter , Doerfel Steffen , Strauss Hans-Georg , Canzler Ulrich , Marth Christian , Reinthaller Alexander , Petru Edgar , Richter Rolf , Rubio Maria Jesus , Bover Isabel , Gonzalez-Martin Antonio , Harter Philipp 
Published: March 2020

5031 Background: We present the efficacy data from a phase III study of topotecan (T) plus carboplatin (C) versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or carboplatin plus pegylated doxorubicin (PLDC). Methods: From 02/07 to 12/09, 590 pts were screened and 550 pts were randomized to either T (0.75mg/m²/d1-3/q21d) + C (AUC 5/d1/q21d) or to standard therapy with CP or GC or PLDC based on patient preference. Progression free survival at 1 year was defined as primary endpoint. Results: Median number of cycles was 6 (range 0-9) in both arms. Most patients preferred GC (78%) in the standard therapy arm.. Best Response (CR+PR) was 73.1% (95%CI) and 75.1% (95%CI) for the CA. Median follow-up was 18 (0-52) months for TC and 20 (0-48) months for standard therapy. TC failed to show any advantage regarding 1-yr.-PFS or OAS. Conclusions: The combination of topotecan plus carboplatin failed to improve PFS or OAS in platinum sensitive relapsed ovarian cancer. In addition, carboplatin plus gemcitabine was well tolerated with lower rates of severe and long-lasting (neuropathy) toxicities compared to paclitaxel-carboplatin. [Table: see text]