bluuebunny/crossref_metadata_2025_split huggingface dataset:
Continuous daily administration of sunitinib in patients (pts) with cytokine-refractory metastatic renal cell carcinoma (mRCC): Updated results
Authors: Srinivas S. , Roigas J. , Gillessen S. , Harmenberg U. , De Mulder P. H. , Fountzilas G. , Vogelzang N. , Peschel C. , Flodgren P. , Escudier B. 
Published: March 2020

5040 Background: Sunitinib malate, an oral, multitargeted tyrosine kinase inhibitor of multiple receptors, showed significant efficacy in 168 pts with cytokine refractory mRCC, with a 42% objective response rate (ORR) and progression-free survival (PFS) of 8.2 months at 50 mg/day (4 weeks on treatment, 2 weeks off) per investigator assessment (Motzer et al. JAMA 2006;295:2516–24). This study was designed to determine the efficacy and safety of single-agent sunitinib when administered in a continuous 37.5 mg/day regimen. Methods: Pts with histologically proven mRCC, refractory to a cytokine-based regimen, were enrolled in this open-label, multicenter, phase II study. Eligibility criteria included measurable disease, ECOG PS 0/1, and adequate organ function. Pts were randomized to receive sunitinib in the morning (AM) or in the evening (PM) at a dose of 37.5 mg/day, with individual doses subsequently titrated based on tolerability. The primary endpoint was RECIST-defined ORR. Secondary endpoints included PFS, adverse events (AEs) and quality of life measures. Results: 107 pts were randomized to AM (54) or PM (53) dosing and have been on study a median of 6.8 months (0.4 to 13.3). As of October 2006, 55 pts have discontinued due to progression (37 pts [35%]), AEs (17 pts [16%]), and 1 consent withdrawal (1%); 47 pts (44%) were dose reduced to 25 mg/day due to grade 2/3 AEs, the most frequent being: asthenia (12%), hand-foot syndrome (8%), and diarrhea (5%). The most commonly reported (=5% of pts) grade 3/4 AEs were hypertension (10%), asthenia (9%), hand-foot syndrome (9%), anorexia (8%), and diarrhea (6%). 31 pts (29%) were maintained on continuous sunitinib at 37.5 mg/day, and 29 (27%) were escalated to 50 mg/day. There were no significant differences between pts who received AM or PM dosing. Quality of life results will be presented. The best response by RECIST per investigator assessment shows an ORR of 19% with 43 pts (40%) with =6 months of stable disease. The median PFS is 8.3 months. Conclusions: Sunitinib 37.5 mg/day continuous dosing has a manageable safety profile and demonstrates promising clinical benefit as second-line therapy in mRCC. This regimen provides alternative sunitinib dosing that can be explored in combination studies. No significant financial relationships to disclose.
Personalized surveillance and prognostication of patients undergoing kidney cancer surgery: The 15-year UCLA experience
Authors: Belldegrun A. S. , Riggs S. , Zomorodian N. , Pantuck A. J. , Klatte T. , Kabbinavar F. F. 
Published: March 2020

5045 Background: Renal cell carcinoma (RCC) is a heterogeneous disease with varying biology, clinical manifestations, and outcome. An evolving understanding of prognostic factors for patients is leading toward individualized surveillance as well as treatment. We reviewed our large single center experience trying to maximize prognostication and surveillance for each patient. Methods: The charts of 1,825 patients with renal masses from 1989–2006 were reviewed and 263 variables/patient were recorded. 1,492 underwent partial or radical nephrectomy with the final histology being RCC. Statistical analysis was performed via Cox regression and concordance models. This enabled us to investigate the Surveillance & Prognosis University of California Integrated Staging System (S&P-UISS), a 3-tiered group system for based on low (LR), intermediate (IR) and high risk (HR) categorization separately for both non-metastatic (NM) and metastatic (M) patients, and to compare its prognostic accuracy with the current TNM classification. Results: Of all patients analyzed 66% were male. A Fuhrman grade of 1, 2, 3 and 4 was assigned to 179 (12.3%), 675 (46.5%), 485 (33.4%), and 114 patients (7.8%), respectively. ECOG performance status was 0, 1, 2 and 3 in 768 (52.1%), 652 (44.3%), 51 (3.5%), and 2 (0.1%), respectively. The disease-specific survival (%) for NM LR (n=326, 22%), IR (n=464, 32%), and HR (n=121, 8%) patients was, respectively, 97, 81, 62 at 5 years; 92, 46, 41 at 10 years; 92, 45, 20 at 15 years. For M LR (n=78, 5%), IR (n=406, 28%) and HR (n=58, 4%) survival was 41, 18, 8 at 5 years; 31, 7, 0 at 10 years; and 31, 0, 0 at 15 years, respectively. Based on concordance statistics, S&P-UISS predicted disease-specific survival better than the 2002 TNM system. Conclusions: The S&P-UISS system is a highly reliable and reproducible predictor of mortality following surgical therapy for localized and metastatic RCC. Surveillance and personal treatments should be individualized for a particular patient based on risk group categorization following surgery for their primary tumor. Accurate prognostication allows personal tailoring for treatments as well as allocation into clinical trials. No significant financial relationships to disclose.
Clinical factors associated with outcome in metastatic renal cell carcinoma patients treated with VEGF-targeted therapy
Authors: Golshayan A. , Choueiri T. K. , Elson P. , Garcia J. A. , Khaswneh M. , Usman S. , Tamaskar I. , Wood L. , Rini B. I. , Bukowski R. M. 
Published: March 2020

5046 Background: Therapy targeted against the vascular endothelial growth factor (VEGF) pathway is a standard of care in metastatic renal cell carcinoma (RCC). Identification of clinical features of patients more likely to benefit from these agents would aid in patient selection and interpretation of clinical trial results. Methods: We reviewed 120 metastatic RCC patients receiving bevacizumab, sorafenib, sunitinib or axitinib on one of eight prospective clinical trials at the Cleveland Clinic Taussig Cancer Center. Clinical features associated with outcome were identified by univariate analysis, and then a stepwise modeling approach based on Cox proportional hazards regression was used to identify independent prognostic factors and form a model for progression-free survival (PFS). A bootstrap algorithm was used to provide internal validation. Results: Forty-one patients (34%) achieved an objective response by RECIST criteria (95% C.I. 27–44%). The median PFS for the entire group was 13.8 months (m) (95% C.I. 10.7–19.0 m). Multivariate analysis identified the following independent adverse prognostic factors (PF) for PFS: time from diagnosis to current treatment <2 years, baseline platelet count >300 K/μL, baseline neutrophil count >4.5 K/μL, baseline corrected serum calcium <8.5 or >10.0 mg/dL and initial ECOG performance status >0. Using these factors three prognostic subgroups were formed based on the number of adverse PF present . Median PFS in patients with 0 or 1 adverse PF was 20.1 m (95% C.I. 19.0–22.3 m) compared to 13 m (95% C.I. 8.6–17.6 m) in patients with 2 adverse PF and 3.9 m (95% C.I. 1.8–7.2 m) in patients with >2 adverse PF. Conclusions: Five independent prognostic factors for predicting PFS were identified and used to categorize patients with metastatic RCC receiving VEGF-targeted therapies into three risk groups. These factors can be readily incorporated to clinical patient care, stratification schema for clinical trials utilizing these novel agents and for interpretation of clinical trial results using VEGF-targeted agents therapy. No significant financial relationships to disclose.
Prolonged survival in patients with persistently elevated tumor markers after chemotherapy for nonseminomatous germ cell cancer
Authors: He Z. , Sun Z. , Liu G. , Manola J. , Loehrer P. 
Published: March 2020

5051 Background: Persistently elevated levels of either AFP or HCG or both after chemotherapy are thought to represent residual viable disease while the normalization of tumor markers predicts favorable outcomes. This study was to evaluate the clinical implication of tumor marker normalization for disseminated nonseminomatous germ cell tumors (GCTs). Methods: This was a retrospective data analysis from two prospective randomized trials (ECOG E4887 and E3887). In E4887, 178 patients with minimal- or moderate-stage disease (Indiana stage) were randomized to receive three cycles of cisplatin plus etoposide with/without bleomycin. In E3887, 304 patients with advanced disseminated GCTs were randomized to receive four cycles of bleomycin, etoposide and cisplatin versus the combination of etoposide, ifosfamide and cisplatin. AFP and HCG were assessed at baseline and after each cycle of chemotherapy. Tumor marker normalization was defined as AFP or HCG normalized after completing chemotherapy. OS and PFS curves were estimated by the Kaplan-Meier method. Multivariate and univariate models, stratified on International Germ Cell Consensus Classification (IGCCCG), were used to assess the impact of marker normalization for patients with abnormal markers at study entry. Results: Median follow-up is 14.8 years. About 40% to 60% of Patients with persistently elevated AFP or HCG after chemotherapy have prolonged PFS and/or OS. In IGCCCG poor risk patients, 35% to 55% of them with persistently elevated AFP or HCG after chemotherapy have prolonged PFS and/or OS. There is a statistically significant difference in OS associated with AFP normalization in both multivariate (p=0.008, HR=0.51 with 95% CI=0.31–0.84) and univariate analysis (p=0.0008, HR=0.43 with 95% CI=0.26–0.71). However, there was no statistically significant difference in OS associated with normalization of HCG in both multivariate analysis (p=0.52, HR=0.84 with 95% CI=0.50–1.41) and univariate analysis (p=0.29, HR=0.76 with 95% CI=0.46–1.26). Conclusions: Patients with persistently elevated AFP or HCG after chemotherapy may still have prolonged PFS and/or OS. Normalization of AFP but not HCG is associated with better OS in patients with disseminated nonseminomatous GCTs. No significant financial relationships to disclose.
A nomogram predicting survival of patients (pts) with metastatic or unresectable urothelial cancer (UC) treated with cisplatin-based chemotherapy
Authors: Bajorin D. F. , Ostrovnaya I. , Iasonos A. , Milowsky M. I. , Boyle M. , Riches J. 
Published: March 2020

5055 Background: Cisplatin-based chemotherapy is the standard of care for pts with metastatic or unresectable UC with phase III studies reporting median survivals of 12–15 months. Even more survival variation exists in phase II studies and this disparity is most frequently due to prognostic factors and not individual regimens. Thus, better tools are needed to predict survival both for individual pts and to balance phase III trials. Nomograms have utility in predicting short- and long-term outcome in muscle-invasive UC treated by surgery but they have not been explored in more advanced UC. Methods: We identified 308 pts with metastatic and/or unresectable UC treated on prospective phase II MSKCC protocols of cisplatin-based therapy containing 3–5 total chemotherapy agents. 203 pts received methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), 45 had ifosfamide, paclitaxel and cisplatin (ITP) and 60 pts received doxorubicin plus gemcitabine (AG) followed by ITP (AG-ITP). Survival distributions were compared across trials. Pre-treatment characteristics were then assessed for impact on survival and a nomogram from a fitted Cox model was created to predict 1-yr, 2-yr, 5-yr and median survival. Results: No difference in median survivals were seen among the 3 regimens; median survival was 14.8 months for MVAC, 18.0 months for ITP and 16.1 months for AG- ITP (p=NS). Median survival for all pts was 12.99 months; 268 pts died and 40 pts were censored. 288 pts had all pre-treatment data. Characteristics most associated with survival included visceral metastases (present versus absent, p=.00001) and Karnofsky poor performance status (≥ 80 versus < 80, p= .0005) followed by hemoglobin (normal versus < normal, p=.01) and albumin (actual values, p<.02). These characteristics were then used to construct a nomogram utilizing all 4 factors to predict probabilities of 1-yr, 2-yr, and 5-yr survival. Conclusions: The number and sequence of drugs utilized in cisplatin-based chemotherapy did not substantially impact survival of pts with advanced UC. A nomogram of pre-treatment clinical factors can predict probability of pt survival at 1 yr, 2yrs, and 5 yrs. This nomogram may also be useful to balance treatment arms in phase III trials. No significant financial relationships to disclose.
Phase I study of continuous oral dosing of an irreversible CYP17 inhibitor, abiraterone (A), in castration refractory prostate cancer (CRPC) patients (p) incorporating the evaluation of androgens and steroid metabolites in plasma and tumor
Authors: Attard G. , Yap T. A. , Reid A. H. , Parker C. , Barrett M. , Raynaud F. , Dowsett M. , Dearnaley D. , Lee G. , De Bono J. S. 
Published: March 2020

5063 Background: Despite androgen deprivation therapy, recent studies indicate high levels of intra-tumor androgens and continued androgen receptor (AR) signalling in CRPC. Methods: A phase I trial to evaluate the safety and tolerability of A administered once daily at 250, 500, 750, 1,000 and 2,000 mg to chemotherapy-naïve CRPC p. Extensive endocrine evaluation and CTC enumeration were undertaken. Tumor biopsies pre- and post-therapy were evaluated for androgen levels and TMPRSS2/ETS gene translocations. To investigate secondary resistance due to activation of a promiscuous AR by raised precursor steroids upstream of CYP17, all p who progressed were offered combination treatment of A with dexamethasone 0.5mg od (D). Results: 15 p were treated in 3-p cohorts with PSA declines >70% in 9/16 p ( table ) and subsequent expansion of the maximum biologically available dose of 1,000mg (19 p treated to date). All p had progressed on LHRH agonists and antiandrogens, 7/15 on diethylstilboestrol and 7/15 on steroids. No dose limiting toxicities were observed and the only = grade 2 toxicity was reversible hypertension (5 pts) due to CYP17 inhibition. Pharmacokinetics were dose-proportional; mean drug clearance was 803L/hour; mean Vd was 11680L; mean elimination half-life was 10.6 hours. At all dose levels, treatment was associated with increased steroid precursor levels upstream of CYP17, including up to a 300-fold rise in corticosterone levels, as well as loss of detection of adrenal androgens. Circulating testosterone levels were in the castrate range (<50 ng/dl) at baseline, rapidly becoming undetectable (<1 ng/dl) in all p. Conclusion: A can be safely administered to CRPC pts with CYP17 suppression and important anti-tumor activity suggesting that at least 60% of CRPC are still hormone driven. Phase II evaluation of 1,000 mg is ongoing. [Table: see text] [Table: see text]
Results of a randomized phase II study of irofulven in hormone-refractory prostate cancer patients that have failed first-line docetaxel treatment
Authors: Berger E. R. , Ciuleanu T. , Hart L. , Chi K. N. , Alexandre J. , Oudard S. , Kahatt C. , Weems G. , Cvitkovic E. , MacDonald J. R. 
Published: March 2020

5068 Background: Currently, no available treatments demonstrate an increase in survival for patients (pts) with hormone- refractory prostate cancer (HRPC) who have failed treatment with docetaxel-based regimens. Previous monotherapy and combination Phase I/II trials with irofulven (IROF) have shown antitumor effects in pts with HRPC, including those with resistance to docetaxel. A randomized phase II study was undertaken in HRPC pts with documented resistance to docetaxel to evaluate the efficacy and safety of IROF regimens compared to mitoxantrone (MITOX). Methods: Pts with metastatic HRPC with documented progression by RECIST or PSA Working Group criteria during or within 3 months of prior docetaxel were randomized to 1 of 3 arms in a 2:2:1 ratio: Arm A: IROF (0.45 mg/kg, Day [D]1, 8 every [q] 3 weeks [w]) and prednisone (PRED; 10 mg qd); Arm B: IROF (0.4 mg/kg D1, 15), capecitabine (CAPE; 2,000 mg/m2 D1–15 q4w) and PRED; Arm C: MITOX (12 mg/m2 q3w) and PRED. Pts were stratified by baseline pain status. Efficacy endpoints included time to progression (TTP), overall survival (OS), and response. Results: Enrollment of 134 treated pts was completed as of Jan 2006 (Arm A/B/C: 53/54/27). Median age: 64/66/63 years, median KPS: 80/90/80, median baseline PSA (ng/mL): 144/136/243, disease-related pain at baseline: 65%/57%/59%, and median number of metastatic sites: 1/1/2. Median pre-study PSA doubling time (days) was 42/44/50. Efficacy: As of Jan 2007, median OS (mos) was 10.1/9.5/7.4 in Arms A/B/C (based on 73% of pt deaths). Preliminary median TTP (mos) was 2.2/3.8/1.8, based mainly on PSA progression. PSA and RECIST responses were 10%/22%/0% and 10%/10%/13%, respectively. Safety: Treatment was well tolerated in all arms. The most frequent Grade 3–4 toxicities (% pts) were asthenia (8%/15%/0%), and vomiting (4%/11%/0%). Grade 3–4 hematological events included neutropenia (22%/15%/61%) and thrombocytopenia (23%/21%/4%). Conclusions: Results to date indicate longer survival, longer TTP, and greater PSA response for IROF/PRED and IROF/CAPE/PRED compared to MITOX/PRED. Based on these data, a larger randomized trial of irofulven in docetaxel resistant HRPC patients is warranted. No significant financial relationships to disclose.
A randomized phase II study of OGX-011 in combination with docetaxel and prednisone or docetaxel and prednisone alone in patients with metastatic hormone refractory prostate cancer (HRPC)
Authors: Chi K. N. , Hotte S. J. , Yu E. , Eigl B. J. , Tannock I. , Saad F. , North S. , Powers J. , Eisenhauer E. ,   National Cancer Institute of Canada—Clinical Trials Group
Published: March 2020

5069 Background: Clusterin, a cytoprotective chaperone protein that promotes cell survival, is associated with androgen independent progression and overexpressed in HRPC. OGX-011 (OGX, developed by OncoGenex Technologies/Isis Pharmaceuticals) is a 2’- methoxyethyl modified phosphorothioate antisense that inhibits clusterin expression in humans at doses of ≤640 mg and potentiates chemotherapy activity in prostate xenografts. The objective of this study was to determine the anti-tumor activity of OGX in combination with docetaxel (DOC) in patients (pts) with HRPC. Methods: Chemo-naive pts with metastatic HRPC were randomized to receive DOC 75mg/m2 q3 weeks + OGX 640mg weekly as a 2-hour IV infusion (Arm A) + prednisone or DOC + prednisone (Arm B). Serum levels of clusterin were assessed serially. A single stage randomized phase II design was employed with PSA response rate (RR) as the primary endpoint (Bubley et al, J Clin Oncol 1999;17:3461). Planned sample size was 40 per arm: Arm A the hypotheses (H0:PSA RR<40% vs. H1:PSA RR>60%) could be tested at 10% β and 10% a, Arm B the true PSA RR could be estimated with half-width of the 90% confidence interval <13% if observed PSA RR was 40%. Results: 82 pts (41/arm) were enrolled from September 2005 to December 2006 at 12 centers. Baseline characteristics are similar in both arms (available to date for 63 pts): median age 67 (range: 49–84), PSA 110 μg/L (5.6–1261), hemoglobin 128 g/L (96–158), alkaline phosphatase 133 U/L (47–1294), LDH 193 U/L (120–741). ECOG performance status was 0 in 49% and 1 in 51%; 67% had bone/nodal disease only and 33% had other metastatic sites. To date, 56 pts have received ≥2 cycles. Toxicity due to OGX included grade 1/2 fevers and rigors in 37% and 67% pts respectively, but other adverse events were similar in both arms. PSA response has occurred in 43%, progression in 9%, and 48% have not yet met criteria for response or progression. Conclusions: Combined docetaxel and OGX is well tolerated in pts with metastatic HRPC and PSA responses have been observed. Pt treatment, follow-up and analysis of serum clusterin levels continue. Results by arm will be available by June 2007. Supported by a grant from the NCI-Canada/Canadian Cancer Society. No significant financial relationships to disclose.
Correlation of 11C-choline PET and PSA values in patients with prostate cancer and biochemical relapse after primary treatments
Authors: Vormola R. , Ortega C. , Montemurro F. , Capaldi A. , Cirillo S. , Gabriele P. , Muto G. , Aglietta M. 
Published: March 2020

5073 Background: 11C-choline PET has demonstrated promising results in the evaluation of suspected recurrence after a primary treatment in prostate cancer (PC) patients (pts). However in pts with asymptomatic biochemical relapse (BR), the timing of PET scan is a subject of controversy. Most authors argue against performing PET scan for rising PSA values <5 ng/ml. Aim of our study was to evaluate if there is a PSA cut-off that significatively correlates to 11C-choline PET positivity. Methods: 68 pts with rising PSA after primary treatment underwent 11C-choline PET. Median age was 68 yrs (range 43–84). Median PSA at the time of PET scan was 2.91 ng/ml (range 0.12- 71.60). Primary treatments were: 27 (40%) radical prostatectomy (RP), 22 (32%) external-beam radiation therapy (EBRT), 13 (19%) RP + adjuvant EBRT, 6 (9%) hormonal therapy. Results: 11C-choline PET was positive in 39/68 pts (57%) and negative in 29/68 (43%). Median PSA values were 1.18 ng/ml (range 0.12–6.47) and 5.14 ng/ml (range 1.33–71.60) in pts with negative and positive PET scan respectively. Median PSA values were statistically different in positive and negative 11C-choline PET (Mann-Whitney U Test. p< 0.001). No positive uptake was seen in pts with PSA <1 ng/ml (12/68); all pts with PSA >6.5 ng/ml had a positive finding; for PSA values between 1 and 6.5 ng/ml (33/68), 11C- choline PET showed a pathological uptake in 18 pts. The Receiver Operative Characteristic (ROC) analysis found that a PSA cut-off of 2.31 ng/ml has a sensitivity of 87% and a specificity of 83% in respect of 11C-choline PET positivity. Conclusions: For PSA values > 2.3 ng/ml the probability to have a positive 11C-choline PET is high in order to recommend to perform the exam in clinical practice, even if further data are needed. On the contrary, we can’t suggest to perform PET scan in pts with PSA <1 ng/ml. No significant financial relationships to disclose.