bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between treatment effects on disease progression (DP) endpoints and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC)
Authors: Delea T. E. , Khuu A. , Kay A. , Zheng J. , Baladi J. F. 
Published: August 2020

5105 Background: Access to safe and effective novel therapies may be expedited if DP endpoints (progression-free survival [PFS], time to progression [TTP], or event-free survival) are established as valid surrogates for OS in pivotal studies in mRCC. While the association between DP endpoints and OS has been established in other cancers, it has not been rigorously examined in patients with mRCC. We assessed the association between treatment effects on DP endpoints and treatment effects on OS in controlled trials of patients with mRCC. Methods: A systematic literature search was conducted (Medline, conference abstracts, references of retrieved studies/ reviews) to identify studies meeting the following criteria: controlled trials in mRCC of IL-2, IFN-α, sunitinib, sorafenib, pazopanib, bevacizumab, temsirolimus, or everolimus; English language; publication date≥1997; median time to DP and OS reported for 2 or more treatment groups. For each treatment group comparison, we calculated the differences in median time to DP and median OS and analyzed the association between the differences in median time to DP and differences in median OS using weighted ordinary least-squares (OLS) regression. Results: A total of 21 studies representing 6182 patients, 52 treatment groups, and 35 comparisons were identified. The median difference between treatment groups in time to DP averaged 1.3 months; the median difference between treatment groups in OS averaged 2.8 months. The correlation between differences in median time to DP and differences in median OS was 0.69 (p < 0.0001). In weighted OLS regression, a 1 month difference in DP was associated with a 1.4 month difference in OS (p < 0.0001, adjusted R-sq = 0.46). Conclusions: In patients receiving treatment for mRCC, treatment effects on DP endpoints are predictive of treatment effects on OS. [Table: see text]
Cost-effectiveness of zoledronic acid in the prevention of skeletal-related events in patients with bone metastases from renal cell carcinoma: Comparison between France, Germany, and the United Kingdom
Authors: Botteman M. F. , Kaura S. 
Published: August 2020

5106 Background: Zoledronic acid (ZOL) significantly reduces the risk of new skeletal-related events (SREs) in patients (pts) with bone metastases from RCC. This study assessed and compared the cost-effectiveness of ZOL in pts with RCC from French, German, and United Kingdom (UK) societal perspectives. Methods: This analysis was based on a retrospective analysis of RCC pts with bone metastases who were enrolled in a 9-mo trial of ZOL or placebo (PBO) plus concomitant antineoplastic therapy. A model was developed to simulate costs and quality-adjusted life-years (QALYs) experienced by study pts. The model included data and assumptions regarding SRE incidence, mortality, drug and administration costs, SRE costs, reduced quality of life (QOL) because of SREs and bone pain, and therapy duration. SRE costs were estimated using diagnosis-related group tariff information and published literature. Consistent with similar economic analyses, it was assumed that QOL decreased 20% to 80% (depending on SRE type) for 1 mo after each SRE experienced. Sensitivity analyses were performed to test the effects of alternate assumptions, with < 30,000/QALY considered cost-effective. Results: Compared with PBO-treated pts (n = 19), ZOL-treated pts (n = 27) experienced 1.07 fewer SREs/pt and gained discounted QALYs of approximately 0.1563 in France and Germany and 0.1575 in the UK. Discounted SRE-related costs were substantially lower among pts treated with ZOL vs PBO (-4,196 in France, -3,880 in Germany, and -3,355 in the UK). After including drug therapy costs, ZOL saved 1,358, 1,223, and 719 per pt in France, Germany, and the UK, respectively. In multivariate sensitivity analyses, ZOL saved costs in 67% to 77% of cases, depending on the country. ZOL resulted in a cost per QALY gained < 30,000 in approximately 93% of cases. Conclusions: Treatment with ZOL reduces SREs, improves QOL, and lowers health-related costs compared with PBO in French, German, and UK pts with bone metastases from RCC. Use of ZOL in these populations therefore provides health-related cost savings and is a cost-effective use of healthcare resources. [Table: see text]
Identification of baseline predictive markers of sunitinib activity using a human cytokine antibody array in patients with metastatic renal cell carcinoma (MRCC)
Authors: Perez-Gracia J. , Prior C. , Guillen-Grima F. , Gonzalez A. , Panizo A. , Segura V. , Grande-Pulido E. , Gurpide A. , Melero I. , Calvo A. 
Published: August 2020

5113 Background: Several drugs are available for treatment of MRCC and predictive markers to select the most appropriate therapy for each patient are needed to improve efficacy and to avoid unnecessary toxicities and costs. Methods: Serum samples were collected prospectively in 31 patients treated with sunitinib at baseline and at the time of response evaluation by RECIST criteria. Serums of 6 patients with extreme phenotypes of marked responses (3) or clear progressions (3) were analyzed with a Human Cytokine Antibody Array (Series 2000, RayBiotech, Norcross, GA. USA) which evaluates 174 cytokines related to angiogenesis and tumor proliferation pathways and has been validated in clinical studies. Cytokine intensity levels were compared between both groups at baseline and after response evaluation and fold-change differences were calculated. Following array data normalization, the most relevant cytokines based on statistical significance and on biological plausibility, were assessed with ELISA in the whole group of patients and the results were correlated with clinical benefit (response or disease stabilization) or progression. Results: 27 of the 174 cytokines varied significantly between patients presenting response or progression. Six of them (TNF-α, MMP-9, ICAM-1, BDNF, SDF-1α and VEGF) were assessed with ELISA in 22 evaluable patients. TNF-α and MMP-9 baseline levels were significantly increased in non-responders and they were significantly associated with progression-free and overall survival respectively. The area under the ROC curves of TNF-α and MMP-9 as predictive factors of sunitinib clinical benefit were respectively 0.8287 and 0.7685, indicating good accuracy. Conclusions: Baseline serum levels of TNF-α and MMP-9 warrant further study as predictive markers of sunitinib activity in patients with MRCC. Selection of patients with extreme phenotypes seems a valid method to identify potential predictive factors of response. [Table: see text] [Table: see text]
A cytokine and angiogenic factor (CAF) plasma signature for selection of sorafenib (SR) therapy in patients (pts) with metastatic renal cell carcinoma (mRCC)
Authors: Heymach J. , Jonasch E. , Wang X. , Du D. Z. , Yan S. , Xu L. , Herynk M. H. , McKee K. S. , Tran H. T. , Tannir N. M. , Zurita A. J. 
Published: August 2020

5114 Background: SR, an oral inhibitor of Raf kinase, RET-receptor (R), VEGFR-1, 2, and 3, PDGFR-β, FLT-3, and c-KIT tyrosine kinases, has been shown to prolong progression-free survival (PFS) in mRCC after cytokine failure. In a phase II trial, mRCC pts were randomized to first line treatment with SR vs. SR plus interferon (IFN) to assess whether combination therapy improved PFS. Both treatment arms showed similar outcomes (Tannir et al, ASCO. 2008). Here we investigated predictive and prognostic biomarkers in plasma. Methods: Pts received SR 400 mg PO BID or same dose SR plus IFN 0.5 MU SC BID. Plasma was collected from 69 pts at baseline (BL; SR 34, SR+IFN 35), 59 on day (D) 28, and 57 pts on D56. We used multiplex bead suspension arrays to measure concentrations of 54 CAFs, including VEGF, PDGFbb, EGF, HGF, MMP-9, and multiple chemokines and interleukins (IL). Osteopontin (OPN), soluble carbonic anhydrase 9 (sCA9), placental growth factor (PlGF), collagen type IV (ColIV) and sVEGFR-2 were measured by ELISA. The primary objective of this analysis was to establish a CAF signature based on a set of individual markers at BL with a significant and differential impact on the association between treatment arm and PFS. Results: Among 52 CAFs available at BL, higher than median EGF concentrations associated with poor outcome independently of treatment arm, whereas low IL-2 had the opposite effect (p = 0.003 for both). Only OPN showed a significant treatment by factor interaction at BL (p < 0.01), suggesting that OPN has a differential effect on PFS in the two arms. Pts with high OPN benefitted more from single agent SR (7.74 vs. 3.93 mos for the combination; p = 0.007), but no differences were found for those with low OPN. Lower than median on-treatment increases in sCA9 (D28, p = 0.01) and GRO-alpha (D56, p = 0.04) on SR only were also associated with a better outcome. A 6-marker CAF signature at BL containing OPN, sCA9, VEGF, sVEGFR-2, ColIV, and TRAIL demonstrated predictive value on PFS. Conclusions: A CAF signature showed potential value in predicting differential benefit from single agent SR vs. SR+IFN in mRCC. Broad-based screening of circulating CAFs may identify predictive and prognostic biomarkers in the context of clinical trials. [Table: see text]
A translational phase II trial of celecoxib plus interferon-alpha (IFN-α2b) in metastatic renal cell carcinoma (RCC) patients (pts) with 3+ COX-2 tumor immunostaining
Authors: Schwandt A. , Garcia J. A. , Elson P. , Wyckhouse J. , Finke J. H. , Ireland J. , Triozzi P. , Zhou M. , Dreicer R. , Rini B. I. 
Published: August 2020

5116 Background: Cyclooxygenase-2 (COX-2) has been correlated with RCC stage and grade, and overexpression can lead to dysregulation of dendritic cells (DC) and CD4+/CD25+/FOXP3+ regulatory T cells (Treg). A previous trial of celecoxib in combination with IFNα2b in RCC (Rini et al, Cancer. 2006) demonstrated an association between more intense COX-2 RCC tumor staining and clinical response. Methods: Pts with cytokine-naïve mRCC with at least 10% maximal COX-2 tumor staining received IFNα2b MU five times/week plus celecoxib 400 mg BID continuously. Baseline tumor tissue was stained for COX-2, CD4+ and CD8+ T cells, Treg and DC (s100 and CD208). Peripheral blood prostaglandin E2 (PGE2), DC and Treg number/function and intracellular T cell cytokine production were measured at baseline, at the end of cycles 2 and 4 and at end of treatment. Activation of DC was assessed by IL-12 and IL-10 mRNA and protein production by ELISA. The primary endpoint was objective response rate (ORR). Secondary endpoints were DC / Treg number and cytokine production changes with therapy. The trial tested a null hypothesis of ORR <20% vs. alternative hypothesis of ORR >40%; beta = 0.8 and alpha = 0.05 (n = 34). Immune parameters were analyzed using non-parametric methods. Results: Fourteen pts have been enrolled; 79% male, median age 62 (range, 43–74) and 64% ECOG performance status 0. All pts had prior nephrectomy and 36% had received prior tyrosine kinase inhibitors (TKI); MSKCC Risk Group was favorable 14%, intermediate 71%, and unfavorable 14%. The ORR was 21% and 69% of pts experienced tumor shrinkage. Median PFS is 4.4 months. Toxicity was as expected for IFN therapy. Baseline 3+ COX-2 staining was associated with elevated peripheral blood PGE2 levels (p = 0.02), reduced DC IL-12 expression (p = 0.04) and reduction in IFN gamma-producing CD3+CD4+ T-cells (p = 0.04) compared to a control group of RCC pts with <10% 3+ COX-2 staining (n = 21). No significant changes in immunomodulatory cells were observed with therapy. Conclusions: COX-2 inhibition in combination with IFNα2b in maximal COX-2-expressing mRCC pts has clinical activity. COX-2 RCC tumor expression promotes an immunosuppressive phenotype. [Table: see text]
Dose escalation by high-dose 3D-conformal radiotherapy (HD-3D-CRT) or low-dose 3D-conformal radiotherapy plus HDR brachytherapy (LD-3D-CRT+HDR-B) for intermediate- or high-risk prostate cancer: Early results of a prospective comparative trial
Authors: Guix B. , Bartrina J. , Tello J. , Quinzanos L. , Lacorte T. 
Published: August 2020

5118 Background: To report early and late toxicity and preliminary biochemical outcome in 445 patients with intermediate- or high-risk clinically localized prostate cancer treated with either HD-3D-CRT or with LD-3D-CRT+HDR-B. Methods: Between December 1999 and October 2005, 445 patients (pts) with PSA'10, Gleason score'6 and/or T2b-T3 N0 M0 prostate cancer entered the study. Pts were assigned to one of the two treatment groups: 76 Gy HD-3D-CRT to the prostate in 38 fractions (group 1; 223 patients) or 46 Gy LD-3D-CRT+ 16 Gy HDR-B given in 2 fractions of 8 Gy (group 2, 222 patients). Both groups were well balanced taking into account patient's as well as tumors’ characteristics. Toxicities were scored by the EORTC /RTOG morbidity grading scales. Special attention to local, regional or distant recurrence, survival, late effects, PSA and testosterone levels and quality of life was done. Results: All pts completed treatment. None pts included in the group 1 or 2 experienced grade 3 rectal toxicity. 28 pts of group 1 (12.5%) and 6 pts of group 2 (2.7%) developed grade 2 rectal toxicity (rectal bleeding or urgency). 15 pts in group 1 (6.7%) and 3 pts in group 2 (1.3%) developed grade 1 rectal bleeding (less than 2 times/week). In group 1 and 2, 81.8%and 95,9% of pts were free from rectal reactions respectively (p < 0.005). 19 pts in each group developed acute Grade 2 urinary symptoms (mainly dysuria), and none experienced urinary retention. No pts (0%) developed Grade 3 or 4 rectal or urinary complications. With a mean follow-up of 55 months, the 5-year actuarial PSA relapse-free survival rates for intermediate- and high-risk group 1 pts were 92 and 91 % respectively and 97 and 96 % for group 2 pts (p < 0.06). Conclusions: High-dose 3D-EBRT +HDR brachytherapy is a safe and effective method of escalating the dose to the prostate without increasing the risk of late effects. Acute and late rectal and urinary complications were significantly reduced with the combined treatment, compared with what was observed with high-dose conventional, 3D-CRT. Short-term PSA control rates tends to be better with in the HDR-boosted patients as spected by higher effective-dose. No significant financial relationships to disclose.
Five-year relapse-free survival and predictors of relapse following preoperative docetaxel and mitoxantrone for high-risk localized prostate cancer
Authors: Rademacher B. L. , Garzotto M. , Higano C. S. , O'Brien C. A. , Janeba N. , Fazli L. , Lange P. H. , Lieberman S. , Beer T. M. 
Published: August 2020

5121 Background: Efforts to incorporate systemic therapy with activity against castration-resistant prostate cancer into the early management of high-risk disease are motivated by persistent risk of relapse when neoadjuvant androgen suppression therapy (AST) is combined with surgery. As docetaxel and mitoxantrone exert anti-tumor effects through distinct cellular mechanisms, this combination has the potential for synergistic activity against prostate cancer. Here we report the 5-year outcomes of patients treated with a novel regimen that combines these agents without AST prior to prostatectomy. We also examined pathologic, biomarker and clinical predictors of early relapse. Methods: 57 high-risk prostate cancer patients were enrolled in a phase I/II study of weekly docetaxel 35 mg/m2 and escalating mitoxantrone to 4 mg/m2 delivered weekly for 3 of every 4 weeks per cycle for 4 cycles over 16 weeks followed by radical prostatectomy. A tissue micro-array constructed from the prostatectomy specimens served to facilitate the exploratory evaluation of biomarkers. The primary end point was relapse-free survival. Relapse was defined as a confirmed serum PSA > 0.4 ng/mL. Results: 54 of 57 pts received all 4 cycles of docetaxel and mitoxantrone prior to radical prostatectomy. Grade 4 toxicities were limited to leucopenia, neutropenia and hyperglycemia. Serum testosterone levels remained stable after chemotherapy. Negative surgical margins were attained in 67% of cases. Lymph node involvement was detected in 18.5% of cases. With a median follow-up of 63 months (range 7 to 86 months), 27 of 57 (47.4%) patients recurred. The Kaplan-Meier progression-free survival at 2 years was 65.5% (95% CI 53.0% to 78.0%) and 49.8% at 5 years (95% CI 35.5% to 64.1%). Pretreatment serum PSA, lymph node involvement, and post-chemotherapy tissue VEGF expression were independent predictors of early relapse. Conclusions: Preoperative combination chemotherapy with docetaxel and mitoxantrone is safe. Approximately half of the high risk pts remain relapse free at 5 years and clinical and molecular predictors of early relapse in this population have been identified. [Table: see text]
Weekly paclitaxel (P) with concurrent external beam radiation (EBRT) and androgen deprivation therapy (ADT) in high-risk prostate cancer (PC) patients with or without prior prostatectomy (RP)
Authors: Wu Y. , Kwok Y. , Mirmiran A. , Goloubeva O. , Mannuel H. , Dawson N. , Amin P. , Hussain A. 
Published: August 2020

5122 Background: EBRT with ADT (4 mos to 2–3 yrs) is standard treatment for high risk PC. In this trial, we evaluated weekly P given concurrently with EBRT and ADT in high risk PC. Methods: For pts undergoing RP, high risk was defined as: pT3 and/or pN+, M0, and/or rising PSA (> 0.5) post RP. For pts not undergoing RP (i.e. locally advanced PC [LAPC]) high risk included: cT2b-4N0, N+, M0; bGS 8–10; bGS ≥ 7 + PSA ≥ 10 but ≤ 150; and/or PSA ≥ 20 but ≤ 150. Treatment included ADT (4 or 24 mos, preplanned based on clinical presentation), P (40, 50, or 60 mg/m2/wk) x 7 with EBRT, and whole pelvis EBRT 45 Gy with 19.8 Gy boost (total 64.8 Gy) to prostate bed in RP pts and 25.2 Gy boost (total 70.2 Gy) to prostate in LAPC pts. Results: Between October 1999 and December 2006, 59 pts (29 W, 28 AA) were enrolled (n = 29 LAPC, n = 30 RP); median age 67 yrs, median PSA at trial entry 5.9 (27.5 LAPC, 1.6 RP), median GS 8. Pts were enrolled at different weekly doses of P: 40 mg/m2 n = 10 pts; 50 mg/m2 n = 31 pts; 60 mg/m2 n = 18 pts. ADT for 4 mos was given in 29 pts and for 24 mos in 30 pts. At 40 mg/m2 67/70 (96%), 50 mg/m2 202/217 (93%), and 60 mg/m2 98/126 (78%) planned doses of P were given. There were no acute grade 4 toxicities. Most common grade 3 toxicities were diarrhea 15%, urinary urgency or incontinence 10%, tenesmus 5%, and leukopenia 3%. Median duration of f/u was 75.3 mos, OS 78%, biochemical progression 24/59 (41%) pts, clinical progression 11/59 (19%) pts. Time to biochemical progression was similar between RP vs. LAPC (p = 0.17), between ADT 4 mos vs. 24 mos (p = 0.61), and between AA vs. W (p = 0.54). Conclusions: This trial establishes the feasibility of tri-modality therapy with ADT, EBRT and weekly paclitaxel in high risk PC, both in RP pts and in LAPC pts with intact prostate glands. The maximum tolerated dose of paclitaxel is 50 mg/m2 /wk when given weekly with concurrent radiation to the pelvis and hormone ablation. No significant financial relationships to disclose.
PITX2 methylation and biochemical recurrence in postradical prostatectomy prostate cancer patients
Authors: Heiden E. , Weiss G. , Banez L. , Freedland S. , Sun L. , Hartmann A. , van Leenders G. , Bangma C. , Ittmann M. , Wheeler T. 
Published: August 2020

5124 Background: PITX2 is a bicoid-related transcription factor induced by the Wnt pathway and required for effective cell-type-specific proliferation during development. We previously reported prognostic potential of PITX2 gene promoter methylation for outcome prediction in breast and prostate cancer (PC) patients. Radical prostatectomy (RP) is potentially curative in patients with clinically localized PC. However, biochemical recurrence (BCR) affects 15–30% of patients undergoing RP. In the current study, we validate PITX2 methylation status as a predictor of BCR following RP. Methods: PITX2 methylation status was assessed in formalin-fixed paraffin-embedded RP tumor tissue samples from 476 patients from four different institutions in USA and Europe using customized microarrays. Associations between PITX2 methylation and BCR were assessed using log-rank test and Cox regression controlling for PC features. Results: In multivariate analysis, patients with a high methylation status were at significantly higher risk for BCR compared to patients with low methylation status (HR = 3.0; 95%CI = 2.0–4.5; p < 10-5). BCR-free survival at five years after surgery was 85% and 61% for patients in the low and high methylation group, respectively. In patients with pathological Gleason 7 tumors, the relative risk of suffering BCR was twice as high for a patient with high PITX2 methylation relative to patients with low PITX2 methylation (HR = 2.0; 95%CI = 1.2–3.3; p = 0.005). Moreover, PITX2 methylation status was significant in the group of patients with tumor involvement of the surgical margins in the prostatectomy specimen. (HR = 3.36, 95% CI: 2.24–5.06, p = 0.001). Conclusions: PITX2 methylation status identifies PC patients most likely to experience BCR. This test independently adds to prognostic information provided by standard clinico-pathological analyses improving stratification of RP patients into high- or low-risk for BCR. This new clinical tool would be of particular benefit in assessment of intermediate-risk patients (Gleason 7) or patients with positive surgical margins wherein risk stratification remains a challenge. [Table: see text]
Gene-based prediction of PSA recurrence for clinically localized prostate cancer patients
Authors: Talantov D. , Jatkoe T. , Bohm M. , Zhang Y. , Stricker P. , Kattan M. W. , Sutherland R. L. , Kench J. G. , Wang Y. , Henshall S. 
Published: August 2020

5132 Background: Accurate estimates of the risk of recurrence are needed for the optimal management of patients with clinically localized prostate cancer. We combined an established nomogram and novel molecular predictors into a new prognostic model of prostate specific antigen (PSA) recurrence. Methods: Gene expression profiles from formalin-fixed, paraffin-embedded (FFPE) localized prostate cancer tissues were analysed to identify genes associated with PSA recurrence. The profiles of the identified markers were reproduced by reverse-transcriptase-polymerase-chain-reaction (RTPCR). The RTPCR profiles from 3 of these genes, along with the output from the Kattan post-operative nomogram, were used to produce a predictive model of PSA recurrence. Results: After variable selection, a model of PSA recurrence was built that combined expression values of 3 genes and the postoperative nomogram. The 3-gene plus nomogram model predicted 5-year PSA recurrence with a concordance index (c-index) of 0.77 in a validation set compared to a c-index of 0.67 for the nomogram. This model identified a subgroup of patients that were at high risk for recurrence which were not identified by the nomogram. Conclusions: This new gene-based classifier has superior predictive power when compared against the 5-year nomogram to assess risk of PSA recurrence in patients with organ-confined prostate cancer. Our classifier should provide a more accurate stratification of patients into high and low risk groups for treatment decisions and adjuvant clinical trials. [Table: see text]