bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase Ib dose finding trial of intravenous panobinostat with docetaxel in patients with castration-resistant prostate cancer (CRPC)
Authors: Rathkopf D. E. , Chi K. N. , Vaishampayan U. , Hotte S. , Vogelzang N. , Alumkal J. , Agrawal M. , Nydam T. M. , Fandi A. , Scher H. I. 
Published: August 2020

5064 Background: Panobinostat (LBH589) is a potent pan-deacetylase inhibitor that has demonstrated activity in both in vivo and in vitro prostate cancer models. Methods: An open-label, multicenter, dose-finding trial of i.v. panobinostat given on Days 1 and 8 (10, 15, and 20 mg/m2) with fixed-dose docetaxel on Day 1 (75 mg/m2) and prednisone (5 mg bid) in a 21-day cycle is being conducted in chemotherapy-naïve patients (pts) with CRPC. All pts have adequate organ function and ECOG performance status (PS) < 1. Pts with significant cardiovascular abnormalities or QTcF >450 msec on screening ECG are excluded. This treatment is continued until disease progression or intolerability. The primary endpoint is determination of the maximum tolerated dose (MTD) of i.v. panobinostat in combination with docetaxel using the Bayesian logistic regression model. Dose-limiting toxicities (DLTs) are defined in first cycle. Results: Twenty-one pts (Cohort 1, n = 8; Cohort 2, n = 10; Cohort 3, n = 3) have been treated, with a median age of 66 yrs (range 50–88), median Gleason score of 9 (range 7–9), and median entry PSA of 67.1 (range 1.3–7920). DLTs include: Gr 4 bradycardia in Cohort 1 (n = 1) and Gr 4 neutropenia, resulting in Day 8 panobinostat dose omission (Cohort 2, n = 2; Cohort 3, n = 1). Gr 3/4 adverse events (AEs) include: neutropenia (n = 12), febrile neutropenia (n = 3), dizziness (n = 2), DVT (n = 1). Other Gr 1 or 2 AEs include: thrombocytopenia (n = 4), fatigue (n = 10), alopecia (n = 7), diarrhea, nausea, and rash (n = 5). Among the 599 ECGs, there was 1 QTcF increase of >60 ms from baseline and no QTcF >480 ms. Preliminary Cohort 1 pharmacokinetic (PK) data shows the mean panobinostat AUC0-inf does not differ between Day 1 (239 ng*hr/mL ) and Day 8 (254 ng*hr/mL), and the mean clearance value appeared to be similar between Days 1 and 8. In Cohort 1, the median number of cycles was 6. Four of 8 pts received >6 cycles. Five and four pts had >30% and >50% PSA reduction from baseline, respectively. In Cohort 2, 9 of 10 pts are still on treatment after 3 cycles. Conclusions: The combination of panobinostat at 10 or 15 mg/m2 with docetaxel is feasible and to date no PK interaction is apparent. Full safety, efficacy, and PK results will be presented. Under DOD PCCTC. [Table: see text]
Value of adjuvant radiation therapy in breast cancer patients with one to three positive lymph nodes undergoing a modified radical mastectomy and systemic therapy
Authors: Dawood S. , Gonzalez-Angulo A. M. , Woodward W. , Meric-Bernstam F. , Hunt K. , Buzdar A. , Hortobagyi G. , Buchholz T. 
Published: August 2020

507 Background: Whether adjuvant radiation therapy should be utilized for patients (pts) with early stage breast cancer with up to 3 positive axillary lymph nodes treated with mastectomy and systemic therapy is controversial. This retrospective study was performed to determine if adjuvant radiation therapy had an impact on survival for this cohort of pts. Methods: 4240 pts with T1–2N0–1 breast cancers, diagnosed between 1980–2007, who underwent either mastectomy without adjuvant radiation therapy or segmental mastectomy with adjuvant radiation therapy were identified. All pts received systemic treatment. Women with >3 positive axillary lymph nodes were excluded. Overall (OS) and distant disease free survival (DDFS) were estimated using the Kaplan-Meir product method. Cox proportional hazards were used to determine associations between OS/DDFS and type of surgery after controlling for pt and disease characteristics. Results: 1336 (18.8%) had T1N0 disease, 1114 (26.27%) had T2N0 disease, 989 (23.33%) had T1N1 disease and 801 (18.89%) had T2N1 disease. Median follow-up was 54 months.5- year DDFS among women who underwent mastectomy and segmental mastectomy was 81% (95% 78%-83%) and 86% (95% CI 84%-87%), respectively (p < 0.0001). In the Cox analysis, pts who had mastectomy without radiation had a significantly increased risk of distant recurrence (HR= 1.39, 95% CI 1.14–1.70, p= 0.0013) than pts treated with segmental mastectomy and radiation. When looking at subgroups, no significant difference in DDFS was observed between the two groups in pts with lymph node negative disease. However, for pts with 1–3 positive lymph nodes, pts treated with mastectomy without radiation had significantly increased risk of distant recurrence compared to pts treated with segmental mastectomy with radiation (HR=1.614, 95% CI 1.198–2.177, p= 0.002). This difference was most pronounce in the subset of patients with T2N1 disease (HR= 1.794, 95% CI 1.220–2.637, p=0.003). Similar trends were observed for OS. Conclusions: This study provides provocative evidence for benefit of radiation therapy among pts with 1–3 positive axillary lymph nodes who are treated with surgery and systemic therapy. No significant financial relationships to disclose.
Cross-validation of a new prognostic index integrating tumor marker decline in patients with relapsed disseminated germ cell tumors
Authors: Massard C. , Huguet H. , Kramar A. , Beyer J. , Hartmann J. T. , Lorch A. , Pico J. , Rosti G. , Droz J. , Fizazi K. 
Published: August 2020

5086 Background: Early serum tumor marker decline during chemotherapy was previously shown to be prognostic for progression-free survival (PFS) and overall survival (OS) in patients with relapsed GCT in an analysis of the IT94 phase III trial, which compared conventional chemotherapy versus high dose chemotherapy (Massard C, ASCO 2008. Abstract No. 5085). The aim of this study was to validate this concept in an independent set of patients. Methods: Data on tumor site, response to first line chemotherapy, serum tumor markers at baseline and after two cycles of chemotherapy were obtained from 235 patients accrued in the IT94 trial (training set) and from 181 patients included in phase III prospective trials of high-dose chemotherapy conducted by the German GCT group (Lorch et al, J Clin Oncol. 2007) (validation set). The change from baseline of serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) was assessed and classified into ‘favorable marker decline‘ and ‘unfavorable marker decline‘ group, as previously described (ASCO 2008. Abstract No. 5085). Results: In both series, favourable serum AFP decline was significantly associated with a better 2-year PFS (46% vs 24%; p < 0.0001) and OS (62% vs 34%; p = 0.0013) while serum hCG decline did not affect outcome. In multivariate analysis of the IT94 trial, an unfavorable AFP decline and a mediastinal primary site were adverse prognostic factors for both PFS and OS, and this was confirmed in the validation set. Among patients from the good prognostic group (favorable AFP decline and non-mediastinal primary site), those who were treated with high-dose chemotherapy had a better PFS (2-year PFS rate: 54% vs 37%; HR = 0.62; p = 0.017), and a trend for a better OS (2-year OS rate: 68% vs. 58%; HR = 0.77; p = 0.29) as compared to patients who were treated with conventional chemotherapy. In contrast, there was no difference in outcome in patients from the poor prognostic group (unfavourable AFP decline and/or mediastinal primary site), whether they received conventional chemotherapy or high-dose chemotherapy. Conclusions: AFP decline during the first 6 weeks of salvage chemotherapy and a mediastinal primary tumor site predict for PFS and OS in patients with relapsed disseminated GCT. No significant financial relationships to disclose.
Laparoscopic renal cryoablation: Risk factor analysis to predict oncologic outcomes with minimum 5-year follow-up
Authors: Kamoi K. , Kawauchi A. , Miki T. , Aron M. , Remer E. , Haber G. , Berger A. , Crouzet S. , Ricardo B. , Gill I. 
Published: August 2020

5094 Background: We analysed risk factors to predict oncologic outcomes at 5–11 year after laparoscopic renal cryoablation (LRC). Methods: Between 09/1997 and 010/2008, we performed renal cryoablation in 340 patients. Of these, 102 patients treated before 10/2003 (all laparoscopic) have minimum 5-year follow-up. Follow-up involved MRI imaging on postoperative day 1, 3 months, 6 months, 12 months, and then annually. Cryolesion biopsy was performed at 6-months. All data were prospectively accrued. Results: In the 102 patients with minimum 5-year follow-up, mean age was 66 years. Mean tumor size was 2.3 cm (0.9–5.0 cm). Median ASA score was 3 and mean BMI was 28. Six patients developed locoregional recurrence, 2 had locoregional recurrence with metastases, and 5 had distant metastases without locoregional recurrence. Overall, there were 7 cancer deaths. In the 69 patients with biopsy-proven renal cell cancer (median follow-up 81 mos; range 60–132 mos), 5-year overall, disease-specific, and disease- free survival was 75%, 92%, and 82%, respectively, while 10-year overall, disease-specific, and disease-free survival was 46%, 83%, and 79%, respectively. On multivariate analysis, previous radical nephrectomy for RCC was the only significant predictor for both recurrence- free survival and cancer-specific survival (p = 0.023 and 0.030, respectively). Relative risk of patients who has a history of radical nephrectomy for RCC treatment was 4.1 (95% CIs, 1.2 to 13.4), and 5.4 (95% CIs, 1.2 to 27.7) for disease-free survival and disease-specific survival, respectively. Conclusions: Laparoscopic renal cryoablation is effective oncologic treatment for renal mass in select patients. Disease-specific survival of 92% at 5-years and 83% at 10-years is possible. Preceding radical nephrectomy for RCC treatment was the only independent predicting factor for both disease-free and disease-specific survival. [Table: see text] No significant financial relationships to disclose.
Failure of initial VEGF-targeted therapy in metastatic renal cell carcinoma (mRCC): What next?
Authors: Vickers M. M. , Choueiri T. K. , Zama I. , Cheng T. , North S. , Knox J. J. , Kollmannsberger C. , McDermott D. F. , Rini B. I. , Heng D. Y. 
Published: August 2020

5098 Background: The characterization and efficacy of second-line targeted therapy in patients with metastatic RCC who failed first-line VEGF-targeted therapy in a population-based setting is of clinical relevance but remains to be assessed. Methods: Provincial registries and clinical databases from seven cancer centers (3 in US and 4 in Canada) identified patients with mRCC who received first-line anti-VEGF targeted therapy between 2005–2007. Patient characteristics, data on second-line therapy and outcomes were analyzed. Results: 645 patients with mRCC who received initial VEGF-targeted therapy were identified (sunitinib, sorafenib or bevacizumab) and had a median follow-up of 25 mos. Of these, 218 patients (34%) received second-line targeted therapy: the median age was 62 yrs (range, 41–87), median KPS was 90%, 90% had prior nephrectomy, 3.8% had non-clear cell histology, 5.8% had brain metastases and 79% had > 1 metastatic site. Second-line therapy included anti-VEGF agents (sunitinib n = 93, sorafenib n = 80, bevacizumab n = 11, axitinib n = 8) and mTOR-inhibiting agents (temsirolimus n = 21, everolimus n = 3). Patient characteristics were similar aside from more non-clear cell histology in patients receiving second-line mTOR-inhibiting agents (14% vs 3% p = 0.045). On multivariable analysis, only a higher baseline KPS score prior to first-line therapy predicted which patients were more likely to receive second-line therapy (p < 0.0001). The median time to treatment failure (TTF) of second-line therapy was 4.9 mos for anti-VEGF therapy and 2.5 mos for mTOR inhibitors (p = 0.014). After adjusting for MSKCC prognostic profile (favorable, intermediate, poor), the hazard ratio for TTF was 0.52 (95%CI:0.29–0.91) in pts receiving anti-VEGF therapy. Overall survival from start of second-line therapy was not different between anti-VEGF or anti-mTOR drugs (14.2 vs 10.6 respectively; p = 0.38). 70 patients (10%) received third-line therapy. Conclusions: Baseline KPS is an independent predictor of receiving second-line targeted therapy. Patients who receive a second-line anti-VEGF drug appear to have a longer TTF than those who receive a second-line anti-mTOR drug. However, patient selection may account for this finding and overall survival was not significantly different. Results of ongoing randomized trials are awaited. [Table: see text]
Serum-sodium as an independent prognostic factor in metastatic renal cell carcinoma
Authors: Jeppesen A. N. , Jensen H. K. , Donskov F. , Marcussen N. , von der Maase H. 
Published: August 2020

5102 Background: Recently, low serum sodium has been associated with poor disease-free and overall survival in localized renal cell carcinoma (RCC) (Vasudev, Clin Can Res. 2008). The present study investigated the prognostic impact of serum-sodium values below normal in patients with metastatic RCC (mRCC). Methods: A cohort of 120 consecutive patients with mRCC received subcutaneous, low-dose Interleukin-2 and Interferon-α at Dept. of Oncology, Aarhus University Hospital, from 2002 to 2004 (Cohort A). Baseline variables were collected retrospectively. Follow up was at least 4 years. Potential prognostic factors were analyzed by univariate and multivariate analyses. Endpoint was overall survival. An independent cohort of 120 consecutive patients with mRCC was used for validation. These patients were treated with interleukin-2 based regimens at the same institution from 1999 to 2002 (Cohort B). Data in this cohort were prospectively collected. Results: In cohort A, the estimated 5-year survival rate was 15% and the median survival was 15.1 months. Serum-sodium ranged between 126 and 144 mmol/l. Twenty-four patients (20%) had serum-sodium levels below normal range (<136 mmol/l). In the multivariate analysis, significant independent risk factors of short survival were serum-sodium below normal value (HR 1.90, CI 1.1–3.2, p = 0.014), high neutrophile count (>7) (HR 1.75, CI 1.1–2.8, p = 0.018), lactate dehydrogenase >1.5 upper normal level (HR 2.09, CI 1.3–3.3, p = 0.002), and number of sites (+3) (HR 1.92; CI 1.3–2.9, p = 0.003). In cohort B, the observed 5-year survival rate was 15% and the median survival was 15 months. Serum-sodium ranged between 128 mmol/l and 146 mmol/l. Seventeen patients (14%) had sodium levels below normal range. In the multivariate analysis, serum-sodium was validated as an independent prognostic factor (HR 2.98, CI 1.54–5.77, p = 0.001). Conclusions: Low serum-sodium is a new, validated, independent prognostic factor in patients with metastatic RCC. No significant financial relationships to disclose.
Two-years biochemical failure-free survival following high intensity focused ultrasound (HIFU) for localized prostate cancer: Prospective single center study of 196 patients
Authors: Pinthus J. H. , Farrokhyar F. , Hassouna M. M. , Woods E. , Orovan W. L. 
Published: August 2020

5117 Background: HIFU is an emerging ablative modality for the treatment of localized prostate cancer with limited reports on oncological outcome. We prospectively analyzed our 2-year results. Methods: 253 consecutive patients (age: 64+8) were treated with a planed single session of HIFU using the Ablatherm integrated imaging model system between January 2006 and June 2008. Patients were followed (median: 12; range 3–24 months) with PSA measurement every 3 months. Patients who received prior radiation or hormonal therapy (n=25) and patient for whom at least 2 consecutive PSA measurements were not available (n = 32) were excluded, leaving a total of 196 patients for analysis. Mean pre-treatment PSA was 6.9+3.3. Biopsy Gleason scores at diagnosis (median 9 cores) were 5, 6, 3+4, 4+3 in 1, 91, 66 and 38 patients, respectively. Biochemical failure (BCF) is reported using the Stephenson (PSA >0.4ng/ml and rising), Horwitz (2 consecutive increases of at least 0.5ng/ml) and Phoenix (nadir+2ng/ml) definitions. Results: 196 patients (age: 64+8) met the inclusion criteria for analysis. 75 had low and 121 had intermediate D'Amico's risk stratification disease. Mean and median absolute PSA nadir levels were 0.28+0.53 and 0.06 ng/ml respectively. It was achieved in median time of 3 months and remained unchanged in 70% of the patients throughout the follow-up. Overall 2 years BCF free rates were 70 % (62–78%), 86 % (81–91%) and 96% (91–99%) according to the Stephenson, Horwitz and Phoenix definitions, respectively; with no significant differences between risk groups. Predictors of BCF were absolute nadir [HR: 3.0 (2.3–3.8)] and pre-treatment PSA [HR: 1.1 (1.0–1.2)]. Conclusions: This is the only study to date that analyzed post HIFU BCF free rates according to post radical prostatectomy definition of BCF. BCF usually occur in the first year and plateau thereafter. Short term results by all BCF definitions are promising with similar results for patients with low and intermediate risk. Pre-HIFU PSA and post-HIFU PSA nadir levels are predictors for BCF. [Table: see text]
Effect of a soluble activin receptor type IIB on androgen-deprivation-induced effects on body composition
Authors: Lachey J. , Koncarevic A. , Ucran J. , Pearsall R. S. , Sherman M. L. , Seehra J. 
Published: August 2020

5133 Background: Androgen deprivation therapy (ADT) is a well-established treatment for hormone sensitive prostate cancer, but is associated with adverse side effects including loss of bone and lean mass and increased adipose mass. Activin receptor type IIB (ActRIIB) signaling is necessary for the negative regulation of lean tissue mass and treatment with a non-signaling, decoy ActRIIB results in a robust increase in lean tissue mass. Methods: Similar to ADT patients, orchiectomized (ORX) mice lose bone and lean mass and gain fat mass. To determine the therapeutic potential of inhibiting ActRIIB signaling to reduce the negative effects associated with ADT, we treated sham-operated (SHAM) and orchiectomized (ORX) mice with RAP-031, a fusion protein comprised of a form of the extracellular domain of ActRIIB linked to a murine Fc. Mice received twice weekly injections for 10 weeks with either vehicle (VEH) or 10 mg/kg RAP-031 (RAP). NMR scanning was used to determine body composition and whole body DEXA scans were performed to determine bone mineral density (BMD). Results: ORX resulted in a 4.4% decrease in BMD, an 18% reduction in lean tissue and a 41.6% increase in adiposity compared to the VEH-SHAM cohort. Both RAP-031treated groups of mice had significantly increased BMD and lean tissue mass and decreased adipose mass compared to their respective VEH groups. However, BMD, lean tissue and adiposity were not significantly different between the VEH-SHAM and RAP-ORX groups. These data illustrate that RAP-031 treatment completely attenuates ORX-induced alterations in bone, lean and fat mass. Conclusions: These data support the hypothesis that treatment with a form of soluble ActRIIB can offset negative side effects of ADT and have significant therapeutic implications for the treatment of patients with prostate cancer. [Table: see text] [Table: see text]
Diabetes and the risk of death in men with favorable or high-risk prostate cancer following radiation therapy
Authors: D'Amico A. V. , Braccioforte M. H. , Moran B. J. , Chen M. 
Published: August 2020

5157 Background: An increased risk of all cause mortality (ACM) has been observed in patients with cancer who have diabetes mellitus (DM) (JAMA 2008:300:2754–2764). Yet, how a diagnosis of DM affects survival across the risk-strata of men with prostate cancer (PC) remains unknown. Methods: The study cohort comprised 7041 men of median age 69.6 years treated with brachytherapy with or without external beam radiation therapy (RT) between 10/97 and 7/07. Short course neoadjuvant hormonal therapy (HT) was used in men with pubic arch interference in order to make them eligible for brachytherapy. Cox regression multivariable analyses were performed in men with Gleason score 8 to 10 disease and also in men with favorable-risk (low or intermediate) disease to assess whether men with DM were at increased risk for ACM compared to men without DM. The hazard ratios (HR) and 95% Confidence intervals (CI) reported were adjusted for age, extent of RT, history of myocardial infarction (MI), use of HT and known PC prognostic factors. Estimates of PC-specific mortality (PCSM) were estimated using a cumulative incidence method. Results: After a median follow-up of 4.1 years, 544 (8%) men had died. In the 466 men with Gleason score 8 to 10 cancers 31% (22/70) of deaths were from PC and a diagnosis of DM was not associated with an increased risk of ACM (Adjusted HR (AHR): 1.1 [95% CI: 0.6 to 2.2]; p = 0.78). However, as shown in the Table , for the 6575 men with favorable-risk disease where only 10% (49/474) of deaths were from PC, there was an increased risk of ACM (AHR: 1.5 [95% CI: 1.2 to 2.0]; p < 0.001) in men with diabetes as compared to those without diabetes. PCSM estimates were significantly higher (p < 0.001) in men with Gleason 8 to 10 as compared to low or intermediate-risk PC reaching 10% and 1% respectively by 7 years. Conclusions: These data highlight the importance of aggressive management of DM in men with favorable-risk PC where death from PC is unlikely. [Table: see text] No significant financial relationships to disclose.
Use of metformin and lifestyle intervention to prevent ADT-related metabolic syndrome in prostate cancer
Authors: Nobes J. P. , Langley S. E. , Laing R. W. 
Published: August 2020

5159 Background: The association between androgen deprivation therapy (ADT) for prostate cancer and metabolic syndrome has been reported, with insulin resistance as the key to its development. This is the first study to investigate the effect of metformin and lifestyle changes on the development of ADT-related metabolic syndrome. Methods: Forty men with any stage of prostate cancer, due to receive ADT with a GnRH agonist, were recruited to a prospective randomised pilot study. The control arm comprised 20 patients receiving ADT alone. Men in the intervention arm (n=20) received ADT with 6 months of metformin, a low glycaemic index diet and a regular aerobic exercise programme. All patients were investigated pre-treatment and at 6 months for the metabolic syndrome, insulin resistance, and related biochemical and physical parameters. Results: After 6 months a significant reduction in metabolic syndrome cases (NCEP ATP III definition) was seen in the intervention arm (p=0.042), with an equal number seen in the control arm as at baseline. There was an increase in HDL cholesterol in both arms, which reached greater significance in the intervention arm (p=0.008) than the controls (p=0.015). The table shows an improvement in abdominal girth, weight, body mass index, and systolic blood pressure in the intervention arm, when measured as a % change over 6 months. Biochemical markers of insulin resistance did not significantly differ between each group. Conclusions: ADT is widely used in prostate cancer, but metabolic complications may be responsible for an increased cardiovascular mortality. The preventative role of metformin and lifestyle changes has been evaluated in this study, showing potential beneficial effects. However, the anticipated increased incidence of insulin resistance and metabolic syndrome has not been demonstrated in men receiving ADT alone, which may be due to small study size. Further studies will ascertain whether overall survival can ultimately be improved by this approach. [Table: see text] No significant financial relationships to disclose.