bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of sunitinib in bevacizumab-refractory metastatic renal cell carcinoma (mRCC): Updated results and analysis of circulating biomarkers
Authors: George D. J. , Michaelson M. D. , Rosenberg J. E. , Bukowski R. M. , Sosman J. A. , Stadler W. M. , Margolin K. , Hutson T. E. , Rini B. I. 
Published: March 2020

5035 Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor with antiangiogenic and antitumor activity. This study evaluated the safety and activity of sunitinib in mRCC patients (pts) previously treated with the VEGF-neutralizing antibody, bevacizumab. Levels of angiogenic biomarkers, including plasma VEGF and soluble VEGFR-3 (sVEGFR-3), were assessed for predictive significance with clinical response. Methods: Pts were required to have mRCC with disease progression following bevacizumab- based therapy, measurable disease, ECOG performance status 0 or 1, and adequate organ function. Pts were treated with sunitinib 50 mg daily in 6-week cycles (4 weeks on, followed by 2 weeks off). The primary endpoint was objective response according to RECIST. Plasma VEGF and sVEGFR-3 levels were measured in pre-treatment samples and at multiple timepoints on study. Results: A total of 61 pts were enrolled. The objective partial response rate was 23% (95% CI: 13%, 36%); 35 pts (57%) demonstrated stable disease. The median duration of response was 36 weeks (95% CI: 26, NA) and progression-free survival was 30 weeks (95% CI: 18, 34). Plasma VEGF levels increased from baseline (3-fold mean elevation), while plasma sVEGFR-3 levels decreased from baseline (40% mean reduction). Pre-treatment VEGF levels were significantly higher in pts (n=34) with <10 weeks between cessation of bevacizumab and start of sunitinib (p<0.001); ELISA specificity suggests that detected VEGF is not bevacizumab-bound. Pre-treatment sVEGFR-3 levels were significantly lower at baseline in responding pts vs. non-responding pts (p<0.0318). A greater reduction in sVEGFR-3 levels was seen in responding pts vs. non-responding pts (p<0.10). Pretreatment VEGF and VEGF fold-changes did not differ according to clinical response. Conclusions: Sunitinib has significant antitumor activity in bevacizumab-refractory mRCC pts, suggesting absence of cross-resistance between bevacizumab and sunitinib. Biomarkers including plasma VEGF and sVEGFR-3 may have predictive potential in sunitinib-treated patients. No significant financial relationships to disclose.
The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial: Safety and efficacy in patients (pts) with prior bevacizumab (BEV) treatment
Authors: Drabkin H. A. , Figlin R. A. , Stadler W. M. , Hutson T. E. , Hajdenberg J. , Chu L. , Trent D. , Campos L. T. , Kelly F. , Bukowski R. M. 
Published: March 2020

5041 Background: Sorafenib (SOR) is an oral multi-kinase inhibitor of tumor-cell angiogenesis and proliferation. Phase III (TARGETs) data have demonstrated prolonged progression-free survival in pts with advanced clear cell renal cell carcinoma (RCC) in whom prior therapy failed. Activity of SOR following treatment with BEV, an anti-vascular endothelial growth factor and antiangiogenic monoclonal antibody, has not been evaluated. Methods: A subset analysis was conducted to describe safety and efficacy in the SOR expanded access program in North America for pts receiving prior BEV. Inclusion criteria for this open-label, nonrandomized trial included advanced RCC; ineligibility for, or lack of access to, other SOR clinical trials; age =15 years; ECOG PS of 0–2; recovery from prior treatment; adequate prior treatment of brain metastases. Major exclusion criteria included life expectancy <2 months; active coronary artery disease, ischemia or hypertension; severe renal impairment requiring dialysis. Pts previously treated with BEV required =28 days from last dose, no =Grade 3 hemorrhagic episode during therapy, and no history of =Grade 2 hemorrhagic event 6 mos prior to BEV treatment. Results: Of the 2,488 pts in ARCCS valid for safety analysis, 289 pts had received prior BEV: 65% male with median age 61 yrs. Grade 3 and 4 toxicities occurring in >2% of prior BEV pts included hand-foot skin reaction 9.0%; fatigue 6.9%; hypertension 4.8%; dehydration, dyspnea, anorexia, and abdominal pain 3.1%; back pain, rash/desquamation, and mucositis 2.8%; pleural effusion and diarrhea 2.1%. Of the 195 BEV-pretreated pts evaluable for response, 152 (77.5%) had stable disease and 5 (2.5%) had confirmed partial responses (PR). There were 26 (13.3%) unconfirmed PRs reported according to RECIST, 4 of which missed a second scan due to US ARCCS enrollment ceasing upon FDA approval of SOR in 12/05. Conclusions: We observed activity of SOR following BEV therapy for advanced RCC. AEs in this subset were generally well tolerated and similar to those in the overall ARCCS population. Further investigation is warranted to elucidate mechanisms for response to SOR following prior antiangiogenic treatment. [Table: see text]
Serum level of vascular endothelial growth factor (VEGF) as an independent prognostic factor in metastatic renal cell carcinoma (MRCC)
Authors: Negrier S. , Chabaud S. , Escudier B. , Ravaud A. , Chevreau C. , Blay J. Y. , Delva R. , Biota C. , Perol D. , Menetrier- Caux C. ,   Groupe Francais d’Immunotherapie
Published: March 2020

5044 Background: The French Immunotherapy Group previously showed that circulating interleukin-6 (IL-6) and VEGF correlate with survival in MRCC patients (pts) (Négrier JCO 2004). We aimed to confirm the prognostic value of IL-6 and VEGF, and to test that of macrophage colony-stimulating factor (M-CSF) and macrophage inflammatory protein 3-alpha (MIP-3a) for survival in MRCC pts of good and intermediate prognoses. Patients and Methods: Pre-treatment samples were obtained from 302 MRCC pts enrolled in 2 parallel multicenter randomized cytokine trials. Baseline serum levels of IL-6, M-CSF, VEGF, and MIP3a were determined by immunoassays; their prognostic value for progression-free survival (PFS) and overall survival (OS) was tested. Characteristics of pts with a 0.15 significance level in univariate analysis (ECOG PS, prior therapy, metastatic sites and biological parameters) were entered in a multivariate Cox model. A backward stepwise procedure discriminated non-influential variables at 0.05 level. Results: Median IL6, VEGF, M-CSF and MIP3a levels were respectively 7.3 (range 0–392 pg/mL), 0.5 (0–2.3 ng/mL), 406 (0–4,785 pg/mL) and 0 (0–1,705 ng/mL). IL6 or M-CSF and VEGF (p<0.0001), or IL6 and M-CSF (p=0.0005) were significantly correlated. Death occurred in 192/302 pts, with 20.9 month median OS. OS was highly correlated with IL6, VEGF and M-CSF (p <0.001) but not with MIP3a (p=0.06) in univariate analysis. Only VEGF remained independently prognostic for OS in multivariate analysis (39% increased probability of death if VEGF level doubled) after adjustment on PS, time from diagnosis to metastasis, number of metastatic sites, pleural metastasis, abnormal sedimentation rate, haemoglobin and LDH levels. Similar results were found for PFS, with a hazard ratio of 1.19 for a 2-fold VEGF increase. Conclusions: The independent prognostic value of serum IL6 level is not confirmed in our cohort that excluded pts with poor outcome, but serum VEGF level appears as an independent prognostic factor, thus supporting the therapeutic interest for these pts of newly available drugs targeting VEGF receptors. No significant financial relationships to disclose.
Safety of VEGF-targeted tyrosine kinase inhibitors in patients (Pts) with metastatic renal cell carcinoma (mRCC) and central nervous system (CNS) metastases
Authors: Unnithan J. S. , Choueiri T. , Garcia J. , Dreicer R. , Laura W. , Bukowski R. , Rini B. 
Published: March 2020

5047 Background: Hemorrhagic complications have been reported in pts treated with various angiogenesis inhibitors, however, reports of intracranial bleeding are rare. Intracranial hemorrhage has been reported during therapy with multitargeted tyrosine kinase inhibitors (TKIs) at higher dose levels during phase I evaluation. Given the occurrence of CNS metastases in RCC and the common use of TKIs, a review of the safety of TKIs in RCC pts with CNS metastases was undertaken. Methods: All pts with mRCC and CNS metastases who were treated with TKIs at the Cleveland Clinic Taussig Cancer Center were investigated. Results: Between 8/2005 and 10/2006, 23 pts with mRCC and CNS metastases were treated utilizing either sunitinib or sorafenib. 7/23 pts received sequential therapy with both TKIs. The median time to development of CNS metastases was 16.0 months (range: 0 - 288 months). Thirteen pts received sunitinib (50 mg daily, 4 out of 6 weeks) and 10 pts received sorafenib (400 mg BID continuously). All 23 pts had known CNS lesions at initiation of TKI treatment and had received prior therapy to the CNS. This consisted of either surgery and whole brain radiation therapy (WBRT; 4pts), WBRT alone (3 pts), conformal radiotherapy in the form or gamma knife or Intensity Modulated Radiation Therapy (13 pts), WBRT and gamma knife (2 pts) or surgical resection alone (1 pt). The median TKI treatment duration (including sequential TKI therapy), was 5.6 months (range: 0.3–20.3 months). No evidence of CNS intratumoral bleeding or other hemorrhagic complications have been observed. Three pts developed new metastatic foci in the brain while on sunitinib. Overall, the median time to progression was 6.5 months (0.9 - 20.3 months). Conclusions: These data suggest sunitinib or sorafenib can be safely administered to RCC pts with previously treated CNS metastases The safety of these agents in patients with untreated CNS lesions is unclear, and therefore pretreatment CNS imaging should be considered. [Table: see text]
Comparison of quality-adjusted survival in patients with advanced renal cell carcinoma receiving first-line treatment with temsirolimus (TEMSR) or interferon-α (IFN) or the combination of IFN+TEMSR
Authors: Parasuraman S. , Hudes G. , Levy D. , Strahs A. , Moore L. , DeMarinis R. , Zbrozek A. S. 
Published: March 2020

5049 Background: In a phase 3, randomized, 3-arm study of TEMSR or IFN or the combination of TEMSR + IFN in the first-line treatment of patients with advanced renal cell carcinoma (RCC) and poor-prognostic features, TEMSR improved overall survival (p=0.0069) and progression-free survival (p=0.0001) vs. IFN (Hudes et al. J Clin Oncol. 2006;24:LBA4). Quality-adjusted survival was a pre-defined endpoint and is reported. Methods: Quality-adjusted time without symptoms and toxicity (QTWiST) was estimated by partitioning overall survival into 3 distinct health states: time with serious toxicity, time with progression, and time without symptoms and toxicity (TWiST). Survival was value-weighted when patients completed quality of life questionnaires (EQ-5D) at weeks 12 and 32, when a grade 3 or 4 adverse event (AE) was reported, upon relapse or progression, or upon withdrawal from the study. Treatment group comparisons used restricted means analyses estimated from censored survival data. Restricted means were computed for duration of each health state by truncating data at median follow-up (17.9 months). Variance and covariance were estimated using bootstrap methods. Results: All 626 randomized patients in the study were included in computation of health state durations. EQ-5D questionnaires were obtained from 260/300 (87%) upon progression and 230/570 (40%) after a grade 3/4 AE. Patients receiving TEMSR alone had 38% greater TWiST than those receiving IFN alone (TEMSR=6.5 months vs. IFN=4.7 months, p=0.00048). There was no significant difference in TWiST between the combination arm and IFN alone (IFN+TEMSR=5.4 months vs. IFN=4.7 months, p=0.1288). Patients receiving TEMSR alone had 23% greater Q-TWiST than those receiving IFN alone (TEMSR=7.0 months vs. IFN=5.7 months; p=0.0015). There was no significant difference in Q-TWiST for the combination arm compared with IFN alone (IFN+TEMSR=6.1 months vs. IFN=5.7 months, p=0.3469). Conclusions: Patients with advanced RCC receiving TEMSR alone had significantly greater quality-adjusted survival than those receiving IFN alone. No significant financial relationships to disclose.
Salvage chemotherapy with high-dose carboplatin and etoposide (HDCE) with peripheral blood stem cell transplant (PBSCT) in patients with relapsed seminoma
Authors: Herbert S. M. , Abonour R. , Einhorn M.D. L. H. 
Published: March 2020

5054 Background: Patients with relapsed seminoma are treated with salvage chemotherapy. Current therapeutic options include cisplatin plus ifosfamide based regimens or high dose chemotherapy with PBSCT. At Indiana University HDCE was usually reserved for third line therapy for relapsed seminoma, unless there were visceral metastases or relapse within 3 months of initial chemotherapy. Methods: Retrospective review of 35 consecutive patients with pure seminoma (median 38 yrs; range 23–56 yrs) that received HDCE with PBSCT from 2/96–12/04. Cytoreductive chemotherapy with 0–2 courses of vinblastine, ifosfamide, and cisplatin (VeIP) preceeded HDCE. Carboplatin dosage was 700mg/m2 for 3 days plus etoposide 750mg/m2 for 3 days. A second course of therapy was given after hematopoietic recovery. Results: Treatment related mortality was seen only in patients that received two or more prior regimens (median age 45 yrs, range 27–56 yrs) and occurred in 4/35 (11%) patients. One man died of AML at 62 months (see table below). 26/35 (74%) are continuously NED (cNED). 15/35 patients received 1 prior regimen and 14/15 (93%) are cNED. 20/35 patients received =2 prior regimens and 12/20 (60%) are NED. 14/35 patients had prior XRT. 10/14 (71%) are cNED. 6/14 patients had prior XRT and =2 prior regimens and 3/6 (50%) are NED. Conclusions: HDCE with PBSCT has a high cure rate even when used as 3rd line or later therapy. Because of the 93% continuous NED rate when used as 2nd line therapy and the increased treatment related mortality when used as 3rd line therapy we now recommend HDCE as initial salvage therapy. [Table: see text] No significant financial relationships to disclose.
The Prostate Cancer Clinical Trials Working Group (PCCTWG) consensus criteria for phase II clinical trials for castration-resistant prostate cancer
Authors: Scher H. I. , Halabi S. , Tannock I. , Morris M. , Higano C. , Kelly W. , Sternberg C. , Eisenberger M. , Martin A. , Hussain M. 
Published: March 2020

5057 Background: The clinical manifestations of castration-resistant metastatic prostate cancer pose challenges to the design of phase 2 trials. In 1999, PSAWG issued a consensus report to standardize phase 2 design and endpoint definitions. A reassessment is reported. Methods: At 4 meetings, and using electronic communication, PCCTWG is seeking consensus on the design and analysis of phase 2 trials that can inform decisions about proceeding to phase 3. Results: PCCTWG recognizes that trial objectives, and details of design and analysis depend on the agent under study. PCCTWG recommends: (i) A standard disease assessment that includes prior treatment history, bone scan, and CT of the chest, abdomen and pelvis; (ii) Revision of eligibility criteria to lower PSA thresholds and serum testosterone levels; (iii) Emphasis on time-to-event endpoints including clinical, biochemical (e.g. PSA) or radiologic progression, recognizing that molecular targeted agents may delay progression without influencing initial response. (iv) Independent reporting of biochemical, radiographic, and clinical outcomes, avoiding grouped categorizations of complete or partial response, or stable disease. (v) Treating for a minimum of 12 weeks before assessing disease status, as the onset of PSA declines are often delayed, verifying that an agent does not influence release of PSA from cells. (vi) RECIST criteria are appropriate for changes in measurable disease, separating nodal and visceral sites. (vii) Changes in bone scan should be reported as “new lesions” or “no new lesions”, confirming findings of progression on a second scan. (viii) Pain and analgesic intake should be assessed using validated scales. (ix) Due to inherent variability, randomization to experimental and control groups is preferred, and innovative designs, e.g. expanding selected arms of randomized phase 2 trials to phase 3. Conclusions: PCCTWG recommends increasing emphasis on time to event endpoints as decision aids in proceeding from phase 2 to phase 3 trials. The recommendations will evolve as data are generated from phase 3 studies on the ability of intermediate endpoints to predict for clinical benefit. Support: MSKCC SPORE (CA 92629), Prostate Cancer Foundation. No significant financial relationships to disclose.
Tumor metabolism, blood flow changes, and prognosis by positron emission tomography: A prospective cohort of locally advanced breast cancer patients
Authors: Dunnwald L. , Gralow J. , Ellis G. , Livingston R. , Linden H. , Specht J. , Doot R. , Lawton T. , Barlow W. , Mankoff D. 
Published: March 2020

506 Background: Breast cancer patients with locally advanced tumors receive preoperative chemotherapy to provide early systemic treatment and assess in-vivo tumor response. Positron emission tomography (PET) has been used to follow tumor response to therapy, as pathologic response is predictive of patient outcome. We evaluated the prognostic utility of serial quantitative PET tumor blood flow (BF) and metabolism measurements. Methods: Fifty-five women with a primary diagnosis of locally advanced breast carcinoma (LABC) underwent dynamic [18F]-FDG and [15O]-water PET scans prior to and at midpoint of neoadjuvant chemotherapy. The FDG metabolic rate (MRFDG), transport (K1), and flux (Ki) parameters were calculated, and tumor blood flow was estimated from the [15O]-water study. Associations between tumor BF and MRFDG measurements and disease-free survival (DFS) and overall survival (OS) were evaluated using the Cox proportional hazards model. Results: Patients that had an increase in BF and K1, from baseline to mid-therapy measurements, had elevated recurrence and mortality risks compared to patients that had reductions in BF and MRFDG values. In multivariate analysis, changes in BF and K1 remained independent prognostic indicators of DFS and OS survival. Conclusions: PET measurements of tumor response prior to completion of neoadjuvant chemotherapy were predictive of patient outcome. Patients that failed to have a decline in BF and K1 experienced higher risks of recurrence and mortality that was largely independent of clinical tumor characteristics assessed in this study. These results suggest that tumor perfusion, measured directly by [15O]-water or indirectly by dynamic FDG PET, is highly predictive of outcome in neoadjuvantly treated breast cancer. No significant financial relationships to disclose.
The impact of the duration of adjuvant hormonal therapy in patients with unfavorable prognosis prostate cancer treated with radiotherapy: Secondary analysis of RTOG 85–31
Authors: Souhami L. , Bae K. , Pilepich M. V. , Sandler H. 
Published: March 2020

5062 Background: RTOG 85–31 was a Phase III trial of androgen suppression for life as an adjuvant to radiotherapy. However not all patients continued on the protocol-mandated long-term hormonal therapy despite no evidence of recurrent disease. This analysis correlates duration of adjuvant hormonal therapy and outcomes among patients who prematurely discontinued long-term hormonal therapy. Methods: The protocol mandated pelvic radiotherapy (60–66 Gy) followed by goserelin 3.6 mg monthly given indefinitely or until disease progression. To avoid potential bias due to early progression/death, only patients who were alive with no evidence of disease at the time of cessation of hormonal therapy were included. There were 377 analyzable patients. Patients were divided in groups based on the hormonal therapy duration (HTD), as follows: = 1 year (27.3%), 1< and =2 years (11.4%), 2< and =4 years (13.3%), 4< and =6 years (10.6%) and > 6 years (37.4%). End-points were overall survival, disease-free survival, disease-free survival with PSA <1.5 ng/mL, disease-specific survival, local failure and distant failure. Cox-proportional hazards regression model was used to test the outcomes among the 5 groups. Results: The median follow-up time of surviving patients is 11.27 years. Pretreatment characteristics by hormone duration groups were well balanced except for age. The median duration of adjuvant hormonal therapy was 3.59 years. For each outcome, there are statistically significant differences among the 5 HTD groups in all outcomes without adjusting for other covariates. Pairwise comparisons show that HTD > 6 year group is significantly associated with having an improved survival and fewer failure events than all other HTD groups (HR < 1, p-value <0.0001). Adjusted for age and stratification variables, the HTD>6 year group remains the only group significantly associated with having fewer failure events in all outcomes. Conclusions: Prolonged HTD of > 6 years is significantly associated with improvements in all end-points studied. Based on these data, decreasing HTD to < 6 years may have a detrimental effect in patients with unfavorable prostate cancer. No significant financial relationships to disclose.
Phase I evaluation of abiraterone acetate (CB7630), a 17 alpha hydroxylase C17,20-Lyase inhibitor in androgen-independent prostate cancer (AiPC)
Authors: Ryan C. J. , Rosenberg J. , Lin A. , Valiente J. , Kim J. , Small E. J. 
Published: March 2020

5064 Background: Abiraterone acetate (Ab) is an oral inhibitor of 17 alpha hydroxylase and C17,20-Lyase, which are important in adrenal androgen synthesis. A phase I study was undertaken to define the maximum tolerated dose (MTD) of Ab in patients (pts) with AIPC, the need for corticosteroid replacement (CSR) and the effects of Ab on hormone levels. Methods: Eligible pts had progressive AIPC by consensus criteria and normal organ and adrenal function. Dose escalations both while fasting and with food range from 250 mg to a maximum planned dose of 2,000 mg per day. Single dose pharmacokinetic (pK) analysis was performed prior to the onset of continuous daily dosing. Results: Sixteen pts have been enrolled, 3 with non-metastatic AIPC and 13 with bone/soft tissue metastases. Median PSA and testosterone levels are 26.7 and 7.7 ng/dL, respectively. Fourteen of 16 received prior ketoconazole. CSR has been required during the first month in 1 pt at a dose level of 500 and in 1 pt in month 3. Two pts experienced syncopal events (grade 3) on Ab, one at 250 mg and one at 500 mg, both after starting CSR. Mineralocorticoid-induced hypertension (grade 2) developed in 4 pts and was treated with aldosterone antagonists. Grade 1 edema has occurred in 3 pts. Testosterone became undetectable in 4/9 pts with available data, the mineralocorticoid deoxycorticosterone rose by a median 6.7 fold on therapy (range 1.5–67 fold). PK suggest maximum concentrations of Ab are achieved within 2 hr post dose with a mean t 1/2 of 7.8 hr, and interpatient variability in AUC and Cmax of approximately 2.5 fold. A decline in PSA by >50% occurred in 7 of 14 patients (50%) completing the initial 28 days of treatment. Five of 9 pts with ketoconazole refractory disease experienced a >50% reduction in PSA. Conclusions: Abiraterone appears to have moderate activity in AIPC pts (including significant activity in pts treated previously with ketoconazole) and an acceptable toxicity profile. CSR has not been consistently required. No significant financial relationships to disclose.