tbuckley/cabot-search huggingface dataset:
A randomized open-label study of gefitinib versus docetaxel in patients with advanced/metastatic non-small cell lung cancer (NSCLC) who have previously received platinum-based chemotherapy
Authors: D. Lee, S. Kim, K. Park, J. Kim, J. Lee, S. Shin, J. Kang, C. Suh, M. Ahn, J. Ahn
Journal: Journal of Clinical Oncology (2008)

8025 Background: ISTANA [IRESSA as Second-line Therapy in Advanced NSCLC - Korea] study compared gefitinib (250 mg/day orally) with docetaxel (75 mg/m2 iv every 3 weeks) in patients (pts) with advanced or metastatic NSCLC pre-treated with platinum- based chemotherapy. Methods: Between September 2005 and September 2006, 161 pts (62% male, 68% adenocarcinoma, 41% never-smoker) were randomized to receive gefitinib or docetaxel. The primary objective was to compare progression-free survival (PFS) between gefitinib and docetaxel at the 1-sided 5% significance level. Secondary endpoints were overall survival (OS), objective tumor response rates (ORR), quality of life (QoL; Functional Assessment of Cancer Therapy-Lung [FACT-L] total score and Trial Outcome Index), symptom improvement (FACT-L Lung Cancer Subscale [LCS]), and safety and tolerability. PFS and OS were compared between the treatment groups by the log-rank test and by unadjusted Cox proportional hazard (Cox) model and adjusting for sex, histology, smoking, stage, and performance status. Results: PFS was longer for gefitinib compared to docetaxel (1-sided p=0.0441). The Hazard Ratio (HR) for PFS derived from the unadjusted Cox model was 0.729 (90% CI 0.533–0.998), favoring gefitinib. Gefitinib significantly improved ORR (28.1% vs. 7.6%; 2-sided p=0.0007). OS appears to be longer for gefitinib pts compared to docetaxel pts (HR 0.61, 95% CI 0.35–1.05), although the number of events is small; follow-up is ongoing. No significant differences between arms were seen in QoL and symptom improvement rate. Adverse events (AEs) were generally mild and consistent with the underlying disease and toxicity profile previously seen with each treatment. Grade 3/4 AEs occurred in 21.0% (gefitinib) and 27.6% (docetaxel) of pts. There was 1 possible treatment-related death in the gefitinib arm. The incidence of interstitial lung disease-type event was 3.7% (n=3) with gefitinib and 3.9% (n=3) with docetaxel. Conclusions: The primary endpoint of PFS was longer with gefitinib. Gefitinib significantly improved the ORR compared with docetaxel. Gefitinib was broadly similar to docetaxel in terms of overall QoL improvement. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology
Modulation of angiogenic biomarkers in patients treated on a phase I study of TRC105 (anti-CD105 antibody) monotherapy for advanced solid tumors.
Authors: Y. Liu, M. Starr, H. Pang, J. Marcello, B. R. Leigh, C. P. Theuer, H. Hurwitz, A. B. Nixon
Journal: Journal of Clinical Oncology (2011)

10565 Background: CD105 (endoglin) is an important mediator of tumor angiogenesis that is upregulated by hypoxia and VEGF inhibitors. TRC105 is an anti-CD105 monoclonal antibody currently being evaluated in clinical trials as an anti-angiogenic cancer therapy. Methods: In this first-in-human phase I study, pts with advanced, incurable solid tumors were treated with escalating doses of TRC105, iv every 2 wks, until disease progression. Serial plasma samples were analyzed via a novel multiplex ELISA platform optimized for cancer patients. 39 candidate biomarkers related to tumor growth, angiogenesis, and inflammation were assayed at baseline (BL), after 1 month, and at end of study (EOS). Results: 19 pts treated with TRC105 at 0.01-1 mg/kg were evaluable for biomarker analysis. Spearman’s rank correlation coefficients were calculated for pairs of analytes with known interactions. Wilcoxon signed rank tests indicated that the following analytes were significantly down-regulated at one month when compared with baseline: IGFBP-3 (p=0.001), VEGF-C (p=0.002), VEGF-D (p=0.003), FGFb (p=0.008), PDGF-AA (p=0.011), PDGF-BB (p=0.039), and PIGF (p=0.045). By EOS, significant increases from the 1 month nadir were observed for the following analytes: VEGF-C (p=0.027), VEGF-D (p=0.034), and IGFBP-3 (p=0.043). Conclusions: This is the first systematic investigation of the effect(s) of TRC105 on angiogenic biomarkers in the clinical setting. Multiplex analyses indicate that TRC105 therapy is associated with down-regulation of key modulators of angiogenesis that later increase at the time of disease progression. Based on these preliminary findings, additional analyses are planned for pts treated at higher TRC105 doses as well as pts treated on phase Ib and phase II studies of TRC105 in combination with VEGF inhibitors and other standard-of-care cancer therapies.
Androgen receptor (AR) modulation strategies for recurrent prostate cancer (PC) without androgen suppression
Authors: A. C. Ferrari, L. Wang, X. Liu, X. Liu
Journal: Journal of Clinical Oncology (2006)

4657 Background: Prostate cancer (PC) progression is tightly linked to aberrant expression and activation of the androgen receptor (AR) gene and protein. Activation of AR is supported by increased/promiscuous ligand-binding to AR and cross-talk with activated growth factor receptor pathways and intracellular second messengers. Overexpression of AR mRNA has been linked to increased Sp1 and/or loss of AR suppressor protein (ARS) binding to the AR promoter (Oncogene, 2004). The purpose of this work was to test the hypothesis that down-regulation of AR levels and inhibition of ligand-dependent and ligand-independent activation can control androgen-dependent (AD) and -independent (AI) PC cells growth and sensitivity to apoptosis. Methods: AD and AI LNCaP cells treated with inhibitors of signal transduction pathways or inhibitors of Sp1, HDAC and/or DNA methylation were assessed for growth and apoptosis in the presence or absence of the anti-androgen bicalutamide. The combination index(CI)(CalcuSyn program) was used to measure activity: CI&gt;1=antagonistic; CI=1, additive; CI&lt;1,synergistic. Pertinent proteins were evaluated by Western blot. AR transactivation by transfection assays using AR and PSA reporter constructs. Results: Combinations of bicalutamide with inhibitors of Akt (Rapmycin), Sp1 (Mithramycin), HDAC (trichostatin A, Sodium butyrate) and DNA methylation (5’-Aza) were synergistic against AD and AI LNCaP cells while EGFR (Iressa) was additive. Decreased AR expression/phosphorylation and transactivation activity preceded the biologic effect. Some triplet combinations enhanced further AR modulation and biologic activity. Conclusion: a global strategy to simultaneously reduce AR levels and activation activity of downstream target genes might be an effective approach against androgen-dependent and androgen-independent clones present in recurrent, high-risk PC patients with potential to spare or postpone the need for castration. No significant financial relationships to disclose.
A phase II study with CP-4055 in patients with second salvage AML
Authors: F. J. Giles, S. O'Brien, D. A. Rizzieri, N. Vey, U. Krug, M. Sekeres, T. F. Jacobsen, B. I. Nilsson, K. Staudacher
Journal: Journal of Clinical Oncology (2009)

7047 Background: CP-4055 (cytarabine 5'-elaidic acid ester) is a novel derivative of cytarabine, independent of nucleoside transporters to enter the cell. The aim of this study was to assess efficacy and safety of CP-4055 when given as second salvage therapy to patients (pts) with acute myeloid leukemia (AML). Methods: Adult pts who received two previous chemotherapy regimens and who had refractory/relapsed AML (CR after first salvage therapy lasting less than 6 months) were enrolled. CP-4055 2,000 mg/m 2 /d was administered over 24 h (CIV) in a day (d) 1–5 q3w schedule. After every 20-pts cohort, an Independent Data Monitoring Committee (IDMC) evaluated the results for futility and safety for recommendation of study continuation. Results: Forty pts (28 male and 12 female, median age 48 yrs [range 26–82]) were enrolled. 6 pts had previous transplant, the majority of the pts had previous ara-C based therapy, 12 pts had not obtained CR1 or CR2. Only 1 pt did not receive d1–5 dosing. The first 20-pt cohort (12 male, median age 53 yrs [range 26–82]) was evaluated by the IDMC. Most frequently reported related AE ≥ grade 3 (CTCAE v3.0) were myelosuppression, abdominal pain, colitis, diarrhoea, nausea, fatigue, liver function test (LFT) elevation. Clinical activity (IWG criteria for AML), 2 CR (1 with no CR1 or CR2), and 1 CRp (CR rate 15%), were reported. Toxicity was manageable, clinical activity reported and continuation recommended. Among all 40 patients 7 pts (18%) had LFT elevations of grade 3 or more and 4 pts (10%) had LFT elevations of grade 2. Clinical activity has been reported also among the last 20 pts. Therapy is ongoing. Conclusions: CP-4055 given as second salvage therapy to AML pts show manageable toxicity when administered at 2,000 mg/m 2 /d, 24 h CIV, in a d1–5 q3w schedule. Clinical activity (2 CR and 1 CRp) has been reported among the first 20 late stage AML pts. Data from 40 patients will be presented. [Table: see text]
MTOR inhibition favors the differentiation of human in vitro-induced regulatory T cell through selective protein synthesis
Authors: Viviana Volta, Amanda Ernlund, Amanda Valeta, Sandra Demaria, Robert J Schneider
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts The immunological composition of the primary cancer, metastatic sites, and stromal tissue determine cancer progression and treatment response. Breast cancers produce cytokines and chemokines that attract and polarize immune cells in a manner that promotes disease progression and
A prospective evaluation of combined modality therapy for breast cancer with ipsilateral supraclavicular node metastases
Authors: R. Dienstmann, H. Noronha Filho, L. G. Branco, C. F. Lima, G. J. Rodrigues, L. C. Freitas, L. M. Rezende, I. A. Small, J. Bines
Journal: Journal of Clinical Oncology (2007)

17025 Background: Based on retrospective data, the most recent breast cancer staging classification changed the status of ipsilateral supaclavicular node mestastases from M1 to N3c. This carried along with it modifications in the treatment of a small subset of breast cancer patients. The aim of this study is to prospectively evaluate surgery and radiation therapy besides systemic treatment in pts with stage IIIC breast cancer. Methods: Phase II single-institution trial. Eligibility: patients with non-metastatic breast cancer and pathological confirmation of ipsilateral supraclaviclular node metastases. Treatment: FAC (fluorouracil 500 mg/m 2 , doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 ) q 21 days × 6; followed by modified radical mastectomy (MRM); adjuvant radiotherapy and tamoxifen (if estrogen and/or progesterone receptors positive - ER/PR). Results: Since May 2002, 22 patients entered the trial, with a median follow-up of 25 months (4–50). Median age was 50 years (29–69). Median tumor size was 6 cm (2.5–15), most patients had T4 disease (77%) and ER/PR positive tumors (64%). All patients underwent MRM after neoadjuvant FAC. Clinical response: 1 (5%) complete, 20 (90%) partial, 1 (5%) minor response. Until December 2006, 13 patients progressed and 7 died. Five patients (23%) had loco-regional relapse and 5 (23%) developed brain metastases. Median estimated progression-free survival was 41 months (14.1–67.8) with median survival not reached. The estimated 2-year progression-free and overall survival rates were 32% and 67%, respectively. Conclusions: Our results, collected in a prospective fashion, are in agreement with previous retrospective studies. Combined-modality treatment for breast cancer with ipsilateral supraclavicular node metastases is recommended. No significant financial relationships to disclose.
Changing rates of organ-preservation therapy over time for head and neck cancer: A SEER-Medicare analysis.
Authors: D. J. Sher, B. A. Neville, R. B. Tishler, D. Schrag
Journal: Journal of Clinical Oncology (2010)

6063 Background: The radical treatment of head and neck squamous cell carcinoma (HNSCC) involves either primary surgery or organ preservation therapy (OPT), the latter accomplished with radiotherapy, with or without concurrent chemotherapy. The objective of this study was to analyze the secular trend in the use of OPT between 2000 and 2005 for patients with HNSCC aged 66-80 years. Methods: A population-based retrospective cohort study utilizing the SEER-Medicare linked database identified 3,674 patients aged 66-80 years with a diagnosis of HNSCC between 2000 and 2005 and treated primarily with surgery or radiotherapy. The primary outcomes were the use of OPT and the use of concurrent chemotherapy, and the primary predictor was treatment era (2000-2001, 2002-2003, 2003-2004). Results were adjusted for patient demographics, disease stage (early vs. advanced), and tumor site using multivariable logistic regression. Results: Among all patients, the rate of OPT increased from 40.6% to 53% between 2000-2001 and 2004-2005 (p < 0.0001). When only including patients with advanced disease, the rates of OPT increased from 46.1% to 58.8% (p < 0.0001). The rates of OPT among early stage patients also increased from 37.3% to 49.3% (p < 0.0001). The rates of OPT for patients with larynx cancer increased from 53.1% to 75.1% over this time period (p < 0.0001). After controlling for patient age, gender, disease stage, tumor site, and geographic region, the rate of OPT nearly doubled between 2000-2001 and 2004-2005 (OR 1.9, p < 0.0001). In patients with advanced disease receiving OPT, the rates of concurrent chemoradiotherapy increased from 12.2% to 27.0% (p < 0.0001).While adjusting for patient age, disease stage, tumor site, and geographic region, the rate of concurrent chemotherapy increased 2.8-fold (p < 0.0001) between 2000-2001 and 2004-2005. Conclusions: The rates of organ preservation therapy in patients with HNSCC has increased significantly between 2000-2001 and 2004- 2005 among Medicare recipients aged 66-80 years. The use of concurrent chemotherapy has also increased substantially over this time, consistent with the publication of randomized trials on this treatment modality. No significant financial relationships to disclose.
Adjuvant chemotherapy with S-1 for patients with head and neck cancer after radical therapy: A phase I/II feasibility study.
Authors: K. Shiga, T. Ogawa, K. Kato, A. Nakanome, T. Kobayashi
Journal: Journal of Clinical Oncology (2010)

e16004 Background: S-1 is a dihydropyrimidine dehydrogenase-inhibitor fluoropyrimidine, which showed a higher response rate in head and neck cancer. However, in general, S-1 was orally administrated for 4 weeks followed by 2-week rest or 2 weeks followed by 1-week rest, relatively high toxic effect of S-1 prevent the long-term administration of S-1 for the patients. Newly developed methods must be needed to achieve stable effects of S-1. Objectives: to determine the safety and efficacy of newly developed S-1 administration method in patients with squamous cell carcinoma of the head and neck after initial radical therapy. Methods: Thirty-three patients with squamous cell carcinoma of the head and neck who were initially treated by surgery or chemoradiotherapy resulting in complete response were into this study. Courses were planned every 4 weeks and up to 12 courses or more. One course consisted of 5 consecutive days of S-1 administration and 2-day rest for first 3 weeks followed by 1-week rest (Tohoku University method). Initially, approximately 80 mg/m2 S-1 was administrated to the patients. Institutional Review Board permitted this study. Results: Eighteen patients continued S-1 administration more than 12 courses. Dosage of S-1 was reduced stepwise in four of these 18 patients. Seven patients showed recurrence and ceased S-1 administration to receive further treatment. Another 8 patients refused to continue S-1 administration mainly because of general dullness and/or appetite loss. Mean of total administration days was 226 days. There were no grade 4 adverse events through this study. Grade 3 events were observed in 3 patients (granulocytes, SGOT and SGPT). The survival at 48 months of the patients who continued S-1 administration more than 12 courses, who refused to continue the study and who ceased due to recurrent tumor was 100%, 38.1%, and 14.3%, respectively. Conclusions: Adjuvant chemotherapy with newly developed S-1 administration method is feasible and active in patients with squamous cell carcinoma of the head and neck after initial radical therapy. No significant financial relationships to disclose.
Risk-based care in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS)
Authors: P. C. Nathan, M. L. Greenberg, K. K. Ness, M. C. Mahoney, J. G. Gurney, M. M. Hudson, S. S. Donaldson, W. M. Leisenring, L. L. Robison, K. C. Oeffinger
Journal: Journal of Clinical Oncology (2007)

6502 Background: Childhood cancer survivors are at significant risk of morbidity as a result of their therapy. Thus, they require regular medical follow-up focused on their specific long-term risks. We examined the frequency and type of care received by a cohort of adult survivors of childhood cancer and examined the predictors of the receipt of appropriate risk-based care. Methods: Eligible subjects were members of the CCSS, a multi-institutional study of patients who have survived at least 5 years after being diagnosed with childhood cancer between 1970 and 1986. Participants completed a baseline survey and a subsequent survey on health care contact within the preceding 2 years. Contact was classified hierarchically as general care, cancer-related care, basic risk-based care and optimal risk-based care. Optimal risk-based care was assessed only in patients whose therapy is associated with a substantial risk of cardiac disease (=300 mg/m 2 of an anthracycline, or any anthracycline plus chest radiation) or breast cancer (females who received chest radiation who are =27 years). Univariate and multivariable analyses were performed to assess associations between demographic/treatment variables and health care outcomes using logistic regression models. Results: The health care questionnaire was completed by 8,448 survivors. Median age (range) at diagnosis was 6.8 (0–21.0) years and at assessment was 31.4 (17.5–54.1) years. 87% reported general medical contact, 31% cancer- related care and 12% basic risk-based cancer care. Amongst patients at increased risk of cardiac disease (N=1,798) or breast cancer (N=852), only 28% reported receiving an echocardiogram and 49% a mammogram, respectively. Patients without health insurance (odds ratio [OR]=2.22, 95% confidence interval [CI]=1.56–3.13, p&lt;0.0001 by Wald statistic), males (OR=1.19, 95% CI=1.03–1.37, p=0.02), younger patients (OR=1.03, 95% CI=1.02–1.04, p&lt;0.0001) and those who perceived their health as good/excellent (OR=1.37, 95% CI=1.13–1.65, p=0.001) were at increased risk of not having received basic risk-based care. Conclusions: Despite a significant risk of late effects after cancer therapy, the majority of adult survivors of childhood cancer do not receive appropriate risk-based health care. No significant financial relationships to disclose.
Dose effect of imatinib (IM) in patients (pts) with metastatic GIST - Phase III Sarcoma Group Study S0033
Authors: C. Rankin, M. Von Mehren, C. Blanke, R. Benjamin, C. D. M. Fletcher, V. Bramwell, J. Crowley, E. Borden, G. D. Demetri
Journal: Journal of Clinical Oncology (2004)

9005 Background: Although IM induces high rates of objective responses and durable disease control in patients (pts) with metastatic GIST, the potential impact of dose on clinical outcomes remains uncertain.At ASCO 2003, this trial reported no differences in progression-free or overall survival between two initial dose levels of IM. The outcomes of pts who crossed over to the higher dose arm are now reported. Methods: Phase III trial in pts with metastatic GIST randomized to one of two dose levels (400 mg vs. 800 mg) of IM daily. The primary aim was to assess the impact of Imatinib dose on overall survival. Pts whose disease progressed on the lower dose were considered to cross over to receive the higher dose IM therapy. Results: As of December 9, 2003, 320 of the initial 746 pts (43%) remain on study. Median follow-up among the 527 surviving pts is now 768 days (range 70–1029); median overall survival has still not been reached for either arm of the trial. Survival estimates at 2 years are 78% (95% confidence interval 73–82%) for the IM 400 arm vs. 73% (95% CI 68–77%) for the IM 800 arm. Progression-free survival at 2 years is estimated at 50% (95% CI 45–55%) vs. 53% (95% CI 47%–58%) (p>0.05) for the 400 vs. 800 mg arms, respectively. 164 pts with initial dose of 400/d have had progression of disease; 88/164 pts with progression at the lower dose have crossed over to the 800/d IM therapy. Median follow-up on crossover therapy is 307 days (range 1–852 d). Following crossover, 5 of 68 evaluable pts (7%) have demonstrated PR and an additional 20 pts (29%) have achieved stable disease. Median progression-free survival and overall survival following crossover are 4 months and 19 months, respectively. Conclusions: This multicenter study continues to demonstrate no significant differences between these two dose levels of IM while supporting the durable survival benefits of this agent in pts with metastatic GIST. The clinical benefit of dose escalation to 800 mg after progression on 400 is unclear, although a subset of pts have had objective benefit with continued IM dosing. Future studies should define the optimal management of GIST pts following limited progression on IM therapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis; Pfizer Novartis Novartis; Pfizer