bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients with previously treated metastatic renal cell carcinoma (mRCC).
Authors: McDermott David F. , Drake Charles G. , Sznol Mario , Choueiri Toni K. , Powderly John , Smith David C. , Wigginton Jon , McDonald Dan , Kollia Georgia , Gupta Ashok Kumar , Atkins Michael B. 
Published: March 2020

4505 Background: BMS-936558 is a fully human monoclonal antibody that blocks the programmed death-1 co-inhibitory receptor (PD-1) expressed by activated T cells. In the initial portion of a phase I study, BMS-936558 showed promising activity in patients (pts) with various solid tumors, including mRCC. We expanded accrual in order to better characterize antitumor and dose effects. Methods: RCC pts were treated with BMS-936558 administered IV Q2WK at 10 mg/kg initially, followed by additional pts at 1 mg/kg. Pts received up to 12 cycles (4 doses/cycle) of treatment or until PD or CR. Clinical activity was assessed by RECIST 1.0. Results: Of 240 pts treated as of July 1 2011, 33 had mRCC and were treated at 1 (n=17) or 10 mg/kg (n=16). ECOG performance status was 0/1 in 13/19 pts. The number of prior therapies was 1 (n=10), 2 (n=9), or ≥3 (n=14), and included prior immunotherapy (n=20) or antiangiogenic therapy (n=24); 31 pts had prior nephrectomy. Sites of metastatic disease included lymph node (n=26), liver (n=7), lung (n=28), and bone (n=10). Median duration of therapy was 19 wk (max 96 wk). The incidence of grade 3-4 related AEs was 12% and included hypophosphatemia (6%), elevated ALT (3%), and cough (3%). Clinical activity was observed at both dose levels (Table). Some pts had a persistent reduction in overall tumor burden in the presence of new lesions and were not categorized as responders. Responses were noted in pts with visceral and bone metastases. Among the responders who were first treated ≥1 yr prior to data lock, 4 of 5 pts treated at 10 mg/kg had OR duration ≥1 yr, and 1 of 2 pts treated at 1 mg/kg was still on study with OR duration of 17.5 mo. Although the data for pts treated at 1mg/kg are not mature, the estimated progression-free survival (PFS) rate at 24 wk in pts receiving 10 mg/kg was 67% (Table). Conclusions: BMS-936558 is well tolerated and has durable clinical activity in pts with previously treated mRCC. Further development of BMS-936558 in pts with mRCC is ongoing. [Table: see text]
Prostate-specific antigen decline (PSA) as a surrogate for overall survival (OS) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) who failed first-line chemotherapy.
Authors: Halabi Susan , Armstrong Andrew J. , Sartor A. Oliver , De Bono Johann Sebastian , Kaplan Ellen B , Small Eric Jay 
Published: March 2020

4515 Background: PSA kinetics, and more specifically a 30% decline in PSA following initiation of first-line chemotherapy with docetaxel, has been reported to be a surrogate endpoint for OS in mCRPC pts. The objective of this analysis was to evaluate PSA kinetics as surrogate endpoints for overall survival (OS) in patients who were receiving second line chemotherapy following progression after docetaxel front line therapy. Methods: Data from a phase III trial of 755 mCRPC pts randomized to treatment with cabazitaxel in combination with prednisone (C+P) every 3 weeks or mitoxantrone in combination with prednisone (M+P) were used. All pts were previously treated with a docetaxel-containing regimen. PSA decline (≥30% and ≥50% ) and PSA velocity within the first three months of treatment were evaluated as potential surrogate endpoints for OS. The proportional hazards (PH) model was used to test for Prentice’s criteria and the proportion of treatment explained (PTE) was computed as a second test of surrogacy. PTE was defined as one minus the ratio of the treatment coefficient in the adjusted PH model (includes PSA decline or velocity) to the treatment coefficient in the unadjusted PH model. Results: Of 755 men, 654 had sufficient PSA data to be included in the analysis. Treatment arm (C+P vs. M+P) was prognostic of OS with a hazard ratio (HR) of 0.65 (95% CI=0.54-0.79, p<0.001). A 30% PSA decline within three months of treatment was associated with a HR of 0.46 (95% CI 0.37-0.57, p-value<0.001) for OS. After adjusting for treatment effect, the HR for 30% PSA decline was 0.50 (95% CI= 0.40-0.62, p<0.001) but treatment arm remained statistically significant thus failing Prentice’s third criterion. The PTE for ≥30% decline in PSA within three months was 0.39 (95% CI= 0.36-0.42) indicating a lack of surrogacy for OS. Similar results were observed for pts who experienced ≥50% decline in PSA and PSA velocity. Conclusions: Neither PSA decline (≥30% and ≥50%) nor PSA velocity within the first three months of therapy are surrogate endpoints for OS in pts receiving second line chemotherapy.
Association of long-term exposure to circulating platinum with adverse late effects in testicular cancer survivors.
Authors: Boer Hink , Proost Johannes H , Nuver Janine , Bunskoek Sophie , Gietema Joyce Q. , Geubels Barbara M. , Altena Renske , Zwart Nynke , Oosting Sjoukje , Uges Donald R.A. , Meijer Coby , De Vries Elisabeth , Gietema Jourik A. 
Published: March 2020

4528 Background: Successful platinum(Pt)-based chemotherapy for testicular cancer (TC) comes at the price of late cardiovascular morbidity and neurotoxicity. Damage induced by circulating Pt could be an etiological mechanism. We investigated the relation between circulating Pt and late effects. Methods: In 96 consecutive TC patients (med age 29 [17-53] at chemotherapy), 3 serum samples and a 24h-urine sample were collected on several time-points med 5 yrs (1-13) after treatment. Pt concentrations ([Pt]) were measured with a sensitive voltammetric method (Lancet 2000, 355:1075). Measured [Pt] combined with cisplatin dose, age, weight and height were analyzed simultaneously to construct a population pharmacokinetic (PK) model using NONMEM. Based on the PK parameters of each patient, individual [Pt] at 1, 3, 5, 10 yrs after start and AUC were calculated. Cardiovascular status, paresthesia and markers of vascular damage were assessed after a med follow-up (FU) of 9 yrs (3-15). Results: Decay of [Pt] was best described by a two compartment model. Mean terminal T1/2 was 3.7 (±0.3) yrs. At all time-points [Pt] correlated with cisplatin dose and renal function during treatment. [Pt] at 3 yrs correlated with systolic blood pressure (BP) (r=.32, p<0.01) and creatinine clearance (CRCL) (r=-.25, p=0.02) at FU. Patients with increased BP had higher Pt AUCs than patients with normal BP (table). Pt AUCs were higher in patients with paresthesia (table). Conclusions: Known late effects of cisplatin-based chemotherapy such as hypertension and paresthesia are related to higher circulating [Pt]. Long-term exposure to Pt is involved in healthy tissue damage in TC survivors. [Table: see text]
Phase III AXIS trial of axitinib versus sorafenib in metastatic renal cell carcinoma: Updated results among cytokine-treated patients.
Authors: Michaelson M. Dror , Rini Brian I. , Escudier Bernard J. , Clark Joseph , Redman Bruce , Tarazi Jamal Christo , Rosbrook Brad , Kim Sinil , Motzer Robert John 
Published: March 2020

4546 Background: Axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, improved progression-free survival (PFS) compared to sorafenib in patients with metastatic renal cell carcinoma (mRCC) in the phase III AXIS trial. In patients previously treated with cytokines, median PFS (mPFS) was 12.1 mo. In a prior phase II study of axitinib for cytokine-refractory mRCC, mPFS was 13.7 mo and the 5-yr overall survival (OS) rate was 20.6%. We report updated PFS and OS for cytokine-treated patients from the AXIS trial. Methods: 723 patients with clear-cell mRCC and progressive disease after 1 systemic therapy were enrolled, of whom 251 received prior interleukin-2 (IL-2) or interferon-α (IFN-α). Patients were randomized 1:1 to axitinib (5 mg twice daily [BID] starting dose) or sorafenib (400 mg BID). Results: As of Jun 3, 2011, mPFS (95% confidence interval [CI]) for cytokine-treated patients was 12.0 mo (10.1, 13.9) with axitinib (n=126) vs 6.6 mo (6.4, 8.3) with sorafenib (n=125): hazard ratio [HR] (95% CI) 0.519 (0.375, 0.720); p<0.0001. For those treated with an IL-2-containing regimen, mPFS (95% CI) was 15.7 mo (8.3, 19.4) with axitinib (n=37) vs 8.3 mo (4.7, 15.7) with sorafenib (n=38). For those treated with IFN-α alone, mPFS (95% CI) was 12.0 mo (10.0, 13.8) with axitinib (n=89) vs 6.5 mo (6.4, 8.2) with sorafenib (n=87). As of Nov 1, 2011, median OS (95% CI) in the cytokine-treated subgroup was 29.4 mo (24.5, not estimable) with axitinib vs 27.8 mo (23.1, 34.5) with sorafenib: HR (95% CI) 0.813 (0.555, 1.191); p=0.144. Adverse event (AE) profiles were similar in both arms. Few cytokine-treated patients (5.6%) discontinued axitinib due to toxicity. AEs reported in >25% of cytokine-treated patients receiving axitinib were diarrhea (49.2%), hypertension (47.6%), fatigue (35.7%), dysphonia (29.4%), and hand–foot syndrome (28.6%). Conclusions: Axitinib showed median PFS and OS of 1 and 2.5 yr, respectively, in cytokine-treated patients, confirming prior phase II study results, and was well tolerated. PFS was superior to that of sorafenib in second-line mRCC and compares favorably with historical results of other agents in second-line mRCC.
Radium-223 chloride (Ra-223) impact on skeletal-related events (SREs) and ECOG performance status (PS) in patients with castration-resistant prostate cancer (CRPC) with bone metastases: Interim results of a phase III trial (ALSYMPCA).
Authors: Sartor A. Oliver , Heinrich Daniel , O'Sullivan Joe M. , Fossa Sophie D. , Chodacki Ales , Wiechno Pawel J. , Logue John P. , Seke Mihalj , Widmark Anders , Johannessen Dag Clement , Nilsson Sten , Hoskin Peter , Bottomley David , Coleman Robert Edward , Vogelzang Nicholas J. , O'Bryan-Tear C. Gillies , Garcia-Vargas Jose E. , Shan Minghua , Parker Chris 
Published: March 2020

4551 Background: Ra-223, a 1st-in-class alpha-pharmaceutical, targets bone metastases (mets) with high-energy alpha-particles of short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) v placebo (pbo) plus BSC in patients (pts) with bone mets in CRPC. The primary endpoint was OS; secondary endpoints included SREs and ECOG PS. Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to 6 injections of Ra‑223 (50 kBq/kg IV) q4 wks or matching pbo and stratified by prior docetaxel use, baseline ALP level, and current bisphosphonate use. Results: 921 pts were randomized from 6/2008-2/2011. In a planned interim analysis (n = 809), Ra-223 significantly improved OS v pbo (median OS 14.0 v 11.2 mo, respectively; two-sided P = .00185; HR = .695; 95% CI, .552-.875).SREs were lower in the Ra-223 v pbo group, and time to 1st SRE was significantly delayed (median time to SRE 13.6 mo v 8.4 mo, respectively; P = .00046; HR = .610; 95% CI, .461-.807). The proportion of pts with ECOG PS deterioration (≥ 2 points) was less in Ra-223 v pbo group at Wk 12 and Wk 24 (4%, 15/389 v 9%, 16/180 and 7%, 16/236 v 12%, 10/83, respectively). Time to ECOG PS deterioration (≥ 2 points) was significantly delayed by Ra-223 v pbo (P = .003; HR = .62; 95% CI, .46-.85). Conclusions: Ra-233 significantly delayed time to 1st SRE and SRE components, notably SCC. Fewer pts in the Ra-223 group had ECOG PS deterioration. Ra-223 improves OS with excellent safety and may provide a new standard of care for CRPC pts with bone mets. [Table: see text]
Development of a nomogram model using a very large sample of patients (pts) to predict the risk of 99mTc-bone scan (BS) positivity in pts receiving androgen deprivation therapy (ADT) for prostate cancer (PCa).
Authors: Gotto Geoffrey , Yu Changhong , Bernstein Melanie , Eastham James Andrew , Kattan Michael W. 
Published: March 2020

4552 Background: Decisions to start imaging pts with PCa can be difficult due to the heterogeneous nature of the disease. Nomograms can combine information on multiple disease factors to improve predictive accuracy and are not influenced by subjective confounders that may affect clinical judgment. However, currently available nomograms for PCa predict current or future risk of positive BS in ADT-naive pts only. We have developed a new nomogram to predict current BS positivity in ADT-treated pts with PCa using a very large pt sample. Methods: All BS records from 1650 ADT-treated pts who received treatment at the Memorial Sloan-Kettering Cancer Center from 2000 to 2011 were analyzed. Pts were followed up from the start of ADT until the first positive BS or last hospital visit. Multivariate logistic regression analysis was used to model the variables that could be used for predicting likelihood of metastases and the variables were incorporated into the nomogram model. The current probability of bone metastasis was generated by the nomogram using the pt variables at each BS and the predictive accuracy was quantified by calculating the concordance index (C-index). Results: In total, 3949 BS records were analyzed and 950 pts had a positive scan. There was an average of 1.1 prior negative scans before a positive result was recorded. Median prostate-specific antigen (PSA) was 2.5 ng/mL and mean PSA doubling time (PSADT) was 7.8 months. At the same time of the positive scans, 49.4% of pts had a PSA <10 ng/mL. Based on clinical relevance and data availability, 13 variables were included in the nomogram model: number of previous negative BSs, PSA, PSADT, prostatectomy, radiotherapy, brachytherapy, chemotherapy, immunotherapy, estrogen therapy, cryotherapy, clinical trial enrollment, and most recent primary and secondary Gleason grades. C-index for the nomogram was 0.76. Conclusions: This is the first nomogram to predict current BS positivity in pts with PCa following ADT. The nomogram was devised from a very large data set from a single center and provides high predictive accuracy.
Development of a needle biopsy-based genomic test to improve discrimination of clinically aggressive from indolent prostate cancer.
Authors: Klein Eric A. , Maddala Tara , Millward Carl , Cherbavaz Diana B. , Falzarano Sara Moscovita , Knezevic Dejan , Novotny William F. , Lee Mark , Magi-Galluzzi Cristina 
Published: March 2020

4560 Background: Standardized, quantitative tools are needed to improve discrimination of clinically aggressive from indolent prostate cancer at diagnosis. We previously identified multiple genes and biological pathways in radical prostatectomy (RP) specimens associated with clinical recurrence and adverse pathology. We evaluated whether measurement of these genes in prostate needle biopsy (Bx) specimens predicts adverse pathology - high grade (GS ≥ 4+3) and/or non-organ-confined disease (pT3) - in a separate study of AUA low-intermed risk pts treated w/ RP. Methods: All AUA low-intermed risk (cT1-T2a, GS 3+3/3+4) pts treated w/ RP <6 mos from Bx at Cleveland Clinic (1999-2007) w/ available Bx tissue and <3 pos cores were evaluated. Expression of 81 prognostic genes identified in previous RP studies and 5 reference genes was quantitated by RT-PCR in 60 µm manually microdissected FPE prostate needle Bx tissue. Association of gene expression w/ adverse pathology was analyzed by logistic regression controlling false discovery rate (FDR) using Storey’s method. Results: RT-PCR was successful for 167 of 171 (98%) pts (92 AUA low, 75 intermed). At RP, 58 pts (35%) had high-grade and/or non-organ confined disease. 58 of 81(72%) genes predicted high grade and/or non-organ-confined disease (FDR<10%), including all stromal response and androgen genes and the majority of cellular organization genes (82%). Proportionately fewer proliferation (40%), stress response (29%), and basal epithelial (25%) genes were associated w/ adverse path. Androgen and cellular organization genes consistently predicted lower risk; stromal response and proliferation genes predicted higher risk; (majority of std odds ratios >1.5, comparable to the prognostic strength of ER in breast cancer). Conclusions: Genes and biological pathways associated w/ clinically aggressive prostate cancer in RP specimens can be reliably measured by RT-PCR from fixed prostate needle biopsies and predict high-grade, non-organ-confined disease. These results support the potential value of a Bx-based assay to inform selection of immediate treatment or active surveillance for pts diagnosed with prostate cancer on needle Bx.
Validation of a genomic-clinical classifier for predicting clinical progression in high-risk prostate cancer.
Authors: Buerki Christine , Mitra Anirban Pradip , Black Peter C. , Ghadessi Mercedeh , Bergstralh Eric J. , Erho Nicholas , Carlson Rachel , Crisan Anamaria , Sierocinski Thomas , Zimmermann Benedikt , Haddad Zaid , Vergara Ismael A. , Ballman Karla V. , Klee George G. , Fink Stephanie , Kollmeyer Thomas M. , Triche Timothy J. , Davicioni Elai , Karnes R. Jeffrey , Jenkins Robert B. 
Published: March 2020

4565 Background: The efficient delivery of adjuvant therapy after radical prostatectomy (RP) in patients with prostate cancer is limited by the lack of biomarkers, beyond clinicopathologic factors, that are able to assess the risk of clinically significant disease progression. Previously, routine FFPE patient specimens from the Mayo Clinic Radical Prostatectomy Registry with long term follow-up were selected to develop a genomic classifier (GC) to predict clinical progression. Here, we present the validation of a GC in a cohort of patients at high risk of disease progression. Methods: A case-cohort study of high-risk RP patients from the Mayo Clinic (N=219) was used to validate the genomic classifier (GC) for predicting clinical progression (defined by positive bone or CT scan post-RP). Its performance was compared to a multivariable clinical classifier (CC) and a genomic-clinical classifier (GCC) which combines GC with established clinicopathologic variables. Concordance index, Cox modeling and decision curve analysis were used to compare the different models. Results: GC and GCC were predictive of clinical progression in the high-risk cohort with c-indices of 0.79 and 0.82, respectively, compared to the clinical classifier (0.70). Multivariable survival analysis showed that the majority of prognostic information of GCC came from the GC with a minor contribution from Gleason score. Decision curve analysis showed that GCC had a higher overall net benefit compared to CC over a wide range of ‘decision-to-treat’ thresholds for the risk of progression. Conclusions: In this high-risk cohort, GC and GCC classifiers showed improved performance over CC in prediction of clinical progression. GC is an independent prognostic factor in this cohort and captures the majority of prognostic information. GC and GCC’s prognostic performance and their usefulness in guiding decision-making in the adjuvant setting after RP need further testing in studies of additional prostate cancer risk groups.
Dual antiangiogenic therapy using lenalidomide and bevacizumab with docetaxel and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Adesunloye Bamidele , Huang Xuan , Ning Yangmin M. , Madan Ravi A. , Gulley James L. , Beatson Melony , Kluetz Paul Gustav , Adelberg David E. , Arlen Philip M. , Parnes Howard L. , Mulquin Marcia , Steinberg Seth M. , Wright John Joseph , Trepel Jane B. , Dawson Nancy Ann , Chen Clara , Bassim Carol , Apolo Andrea Borghese , Figg William Douglas , Dahut William L. 
Published: March 2020

4569 Background: Previously, we had shown the potent anti−tumor activity of dual anti-angiogenic therapy by combining bevacizumab (B) and thalidomide (T) with docetaxel (D) and prednisone (P) in mCRPC (Ning JCO 2010). We hypothesized that combining lenalidomide (L), an analogue of T, with B, D, and P would have a more favorable efficacy/toxicity profile. Methods: All patients (pts) had chemotherapy−naïve mCRPC. Among the first 52 pts, 3 received L 15 mg daily, 3 had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21−day cycle (C). The protocol was recently amended to enroll 11 more pts at L 15 mg; 2 pts have now been enrolled in this expansion cohort. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. PSA each C with imaging after C2 and after every 3C. Dental exams with mandible CT scan at baseline, after C5, and every 6C. Results: 54 of 62 pts have been enrolled. Median age 65.5 (51−82), Gleason score 8 (5−10), on−study PSA 85.2 ng/ml (0.15−3520), and pre−study PSA doubling time 1.49 months (0.52−6.73). Median number of Cs was 16 (3−38). PFS was 22 months and probability of survival at 12 months was 90%. Forty-six (85.2%) and 42 (77.8%) pts had PSA declines of ≥50% and ≥75%, respectively. Of 30 pts with measurable disease there were 1 CR and 25 PR (86.7% overall RR). 17/54 pts were off study for radiographic disease progression and 8/54 for other reasons. Grade ≥2 toxicities included neutropenia (34/54), anemia (23/54), thrombocytopenia (7/54), hypertension (12/54), perianal fistula (3/54), rectal fissure (1/54), myocardial infarction (1/54), and osteonecrosis of the jaw (ONJ) (12/54, 22.0%). At the time of diagnosis of ONJ, 7/12pts were on bisphosphonates (BP), 2/12 had used BP previously, and 3/12 never used BP. The incidence of ONJ was comparable to 18.3% reported by Ning et al. A recent study of carboplatin plus weekly docetaxel reported an incidence of 29.3%. Conclusions: Dual anti-angiogenic therapy with, B and L, plus D and P was associated with high PSA (85.2%) and tumor (86.7%) responses in mCRPC, with manageable toxicities. The incidence of ONJ is comparable to other studies.
Preliminary quality-of-life outcomes for SWOG-9346: Intermittent androgen deprivation in patients with hormone-sensitive metastatic prostate cancer (HSM1PC)—Phase III.
Authors: Moinpour Carol , Berry Donna Lynn , Ely Benjamin , Tangen Catherine M. , Higano Celestia S. , Picus Joel , Schellhammer Paul F. , Skinner Eila C. , Cher Michael L. , Thompson Ian Murchie , Hussain Maha 
Published: March 2020

4571 Background: The relative quality of life (QOL) for patients with newly diagnosed, metastatic prostate cancer, treated with intermittent androgen deprivation (IAD) has been assumed and hypothesized, yet never compared in a well-powered randomized trial (RT) to continuous androgen deprivation (CAD). SWOG-9346 provided such a RT in which to test QOL differences between CAD and IAD in men with metastatic prostate cancer. Methods: Patients were randomized to CAD or IAD. Patients completed the SWOG QOL Questionnaire (SF-20/SF-36, Symptom Distress Scale, treatment-specific symptoms, global QOL) at randomization and months (mo) 3, 9, and 15 post-randomization. Five QOL change scores at one time point (mo 3) were designated as primary for the QOL endpoint and are reported in this abstract: impotence, libido, energy/vitality (E/V), physical function (PF), and emotional function (EF). Significance level was adjusted for 5 comparisons (used p=0.01). Results: 615 patients in the CAD arm and 633 in the IAD arm completed the QOL questionnaire at baseline. Change between baseline and 3 months differed for the two arms with CAD reporting statistically significantly more impotence and less libido than IAD. EF was also slightly better for the IAD arm. Conclusions: These results indicate better sexual function in men receiving IAD versus CAD through post-randomization month 3. Additional benefits for IAD may include better PF, E/V and EF. Ongoing analyses will address the role of missing data, additional follow-up assessments, and resumption of therapy in the IAD arm. [Table: see text]