tbuckley/cabot-search huggingface dataset:
Effect of abiraterone acetate (AA) on patient-reported pain in metastatic castration-resistant prostate cancer (mCRPC) post-docetaxel: Results of longitudinal sensitivity analyses.
Authors: Yanni Hao, Charles S. Cleeland, Dennis Gagnon, Derek Espindle, Arturo Molina, Ethan M. Basch
Journal: Journal of Clinical Oncology (2013)

9618 Background: The COU-AA-301 phase 3 trial showed that AA + prednisone (P) improved overall survival in mCRPC patients (pts) post-docetaxel. Compared with P alone, AA + P also had significant benefits on patient-reported pain. Here we describe post hoc sensitivity analyses of pain data from that trial, using different methods to compensate for the potential impact of missing data. Methods: Pts with mCRPC progressing after docetaxel-based chemotherapy were randomized 2:1 to AA + P or placebo + P. Pain intensity and interference of pain with daily activities were assessed with the Brief Pain Inventory-Short Form (BPI-SF) questionnaire at baseline, Day 15 of Cycle 1, and Day 1 of each 28-day treatment cycle thereafter until treatment discontinuation. The effect of treatment on BPI-SF scores was analyzed using repeated measure mixed-effects (RMM) models, piecewise linear mixed-effects (PWLME) models, and joint mixed-effects and log time-to-dropout (JMEL) models. RMM and PWMLE models assumed missing data (due to death, study dropout, or administrative issues) to be missing at random, the JMEL model to be missing not at random. Model results were compared between treatment arms. Results: 797 pts were randomized to AA + P, and 398 to P only. RMM model estimates suggested statistically significant (p &lt; 0.05) differences in change from baseline for pain intensity and pain interference scores in favor of AA + P at the majority of study visits through cycle 11. PWLME models yielded significantly smaller areas under the curve (AUCs) for AA + P vs P for pain intensity (p = 0.0031) and pain interference (p = 0.0006); smaller AUCs reflect better pain outcomes. Results using JMEL models were nearly identical to those with PWLME models, with AUCs for AA + P significantly smaller than for P alone for pain intensity (p = 0.0031) and pain interference (p = 0.0007). Conclusions: Using various modeling methods that assess the impact of missing data, AA + P showed superior patterns of pain outcomes over time compared with P only in mCRPC pts refractory to docetaxel. These results support the previously reported pain benefits of AA + P over P alone from the same trial. Clinical trial information: NCT00638690.
Survival among advanced non-small cell lung cancer patients with poor performance status after first-line chemotherapy.
Authors: Ramzi George Salloum, Thomas J Smith, Gail Jensen, Jennifer Elston-Lafata
Journal: Journal of Clinical Oncology (2012)

e18144 Background: Evidence-based guidelines recommend chemotherapy for medically fit patients with advanced stage non-small cell lung cancer (NSCLC). Performance status (PS) is a commonly used factor in determining the appropriateness for chemotherapy for this group of patients.The prevalence of poor PS and impact of chemotherapy on survival among NSCLC patients has not been studied in community populations. Methods: Insured patients, aged 50+ years, diagnosed with advanced stage NSCLC between 2000 and 2007 were identified via tumor registry (n=292) and linked to medical record abstracted PS, automated medical claims, and Census tract information. A multivariate Cox proportional hazards model was used to determine the factors associated with survival. Tests of statistical significance were two sided. We defined PS 3 or 4 as “poor” since the NCCN and ASCO guidelines agree that those patients should not routinely receive chemotherapy. Results: Of 292 stage IIIB-IV patients, 82 (28%) had PS 3 or 4, and 39% of PS 3-4 patients received first line chemotherapy. Those who received chemotherapy lived 4.8 months compared to 2.4 months for those who did not. Factors associated with a reduced likelihood of death included receipt of chemotherapy (hazard ratio [HR], 0.67) and surgery (HR, 0.27), and female gender (HR, 0.69). Conclusions: In advanced stage NSCLC, poor PS is common, and oncologists are treating about 40% of those patients with the same drugs as for PS 0-2. Modern chemotherapy is associated with positive effects on survival for poor PS patients, as for good PS patients, but we cannot tell if this is due to chemotherapy or some other factor. Further trials, especially randomized trials, in this common but neglected subgroup are indicated.
Thymidylate synthase (TS) gene polymorphisms affect disease free- (DFS) and overall (OS) survival of colorectal cancer (CRC) patients treated with adjuvant 5-fluorouracil-folinic acid (FUFA)
Authors: E. Hitre, V. Adleff, B. Budai, E. Szabó, Z. Horvath, I. Lang, F. Czeglédi, Z. Orosz, A. Gazdag, J. Kralovanszky
Journal: Journal of Clinical Oncology (2004)

3581 Background: TS, the target enzym of 5-FU has a 28 bp polymorphism in the promoter region containing commonly double of triple tandem repeats of a 28 bp sequence (2R or 3R), and a 6bp ins/del polymorphism on the 3'UTR. Our aim was to study the influence of these TS polymorphisms on tumor response to adjuvant FUFA therapy in CRC patients. Methods: : 89 CRC patients receiving adjuvant FUFA were involved in the study. FUFA was given as bolus (Mayo regimen) or continuous infusion (de Gramont protocoll). TS polymorphisms were determined by PCR PAGE and RFLP method. Results: DFS was significantly longer (p=0,036 logrank test) in patients with +6/+6,+6/-6 genotypes than in –6/-6 genotype.OS was significantly longer (p=0,025) in 3/3 genotype than in 2/3and 2/2 genotype. In rectal cancer +/+ and +/- 3'UTR patients had longer OS than -/- patients (p=0,007).No significant correlation between gene polymorphisms, age, gender, and localization were found. Conclusions: Both TS polymorphisms studied do affect the clinical outcome of the disease in CRC patients treated with adjuvant FUFA chemotherapy. Supported by the NKFP1/48/2001 grant. No significant financial relationships to disclose.
MIMEB: A phase II trial to evaluate FDG-PET/FLT-PET, DCE-MRI and molecular biomarkers for early prediction of nonprogression in patients with advanced non-small cell lung cancer treated with erlotinib and bevacizumab.
Authors: Matthias Scheffler, Marc Christiaan Allardt Bos, Martin L. Sos, Lukas Carl Heukamp, Lucia Nogova, Katharina Koenig, Masyar Gardizi, Christian Mattonet, Deniz Kahraman, Carsten Kobe, Ronald Boellaard, Adriaan A. Lammertsma, Thorsten Persigehl, Walburga Engel-Riedel, Karin Toepelt, Bernd Neumaier, Reinhard Büttner, Thomas Zander, Juergen Wolf
Journal: Journal of Clinical Oncology (2014)

e19049^ Background: Molecular imaging tools gain in importance for assessment of pharmacodynamics, pharmacokinetics, prognosis and prediction of therapeutic outcome in patients with advanced NSCLC treated with targeted therapy. We set up a prospective clinical trial in order to assess the predictive value of early changes in tumor metabolism (by FDG-PET), proliferation (by FLT-PET), and tumor vascularization (by DCE-MRI) noninvasively during therapy with erlotinib and bevacizumab in previously untreated patients with advanced non-squamous cell NSCLC. Methods: Patients with non-squamous NSCLC stage IV without prior systemic therapy received at least six weeks of combined erlotinib and bevacizumab. FLT and FDG-PET scans as well as DCE-MRI-scans were performed at baseline, after one week of therapy and after six weeks of therapy. Standard uptake values (SUVs) of the PET scans and vascularization parameters of the DCE-MRI scans were analyzed, coregistrated and compared with each other. The molecular markers were assessed using next-generation sequencing (NGS) and staining for an angiogenic phenotype. Results: Changes in FDG and FLT uptake after 1 week of therapy predicted nonprogression after 6 weeks of therapy with an area under the ROC curve of 0.75 (p=0.02) and 0.72 (p=0.045), respectively, in 38 evaluable patients. In 86% of the patients, ktrans in DCE-MRI showed a reduction after one week of therapy, while repeated baseline assessments showed reproducibility in a subset of patients. Beside patients with sensitizing EGFR mutations, clinical benefit could be seen in patients with PIK3CA, KRAS and ALK mutations. In these patients, both reduction of PET tracer uptake and ktrans in DCE-MRI could be detected. Conclusions: Imaging-based predictive biomarkers to identify the subpopulation of patients with pronounced benefit of the combination of erlotinib with bevacizumab were successfully added to the molecular-based selection of patients. Results of the ongoing analysis for evaluation of imaging analysis and correlation with tissue-based biomarkers will be presented. Clinical trial information: NCT01047059.
Clinical trial and compassionate use experience with glucarpidase for methotrexate toxicity.
Authors: Brigitte C. Widemann, Nalini Jayaprakash, Scott C. Howard, Claire Daugherty, Nikhil Chauhan, Thomas King, Janet Rush
Journal: Journal of Clinical Oncology (2012)

6530 Background: High dose methotrexate (MTX) is used to treat acute lymphoblastic leukemia (ALL), osteogenic sarcoma, non-Hodgkin lymphoma (NHL), and other cancers. MTX-associated renal impairment with delayed MTX elimination develops after 2 to 10% of treatment cycles, exposing patients to elevated MTX concentrations with potential for enhanced MTX toxicity and prolonged hospitalization. Glucarpidase, a recombinant form of carboxypeptidase G2, rapidly hydrolyzes MTX into inactive metabolites and provides an alternate way of clearance in patients with delayed MTX elimination. Methods: From November 1993 to June 2009, 492 patients experiencing renal toxicity and delayed elimination of MTX were treated with glucarpidase (50 U/kg intravenously) in compassionate use trials conducted in the US and EU. Their outcomes are presented here. Results: The median age of the 492 patients was 18 yrs (range: 5 wks to 85 yrs). Sixty-three percent were male. Forty-one percent had NHL, 30% osteogenic sarcoma, 23% ALL, and 7% other malignancies. The median pre-glucarpidase MTX concentration was 17 µmol/L. Seventy-six percent of patients received 1 dose of glucarpidase, 22% received 2 doses, and 2% received 3 doses. The first dose of glucarpidase was given at a median of 3 days after MTX administration. One-hundred and fifty-six patients had MTX concentrations determined by HPLC. At the first measurement (median 15 minutes post-glucarpidase) MTX was reduced by a median of 99% relative to the pre-glucarpidase baseline. At the last measurement (median 40 hrs post-glucarpidase) median MTX reduction remained at 99% compared with baseline. In 410 patients with pre-glucarpidase renal impairment measured as CTCAE Grade 2 or higher, 64% recovered to Grade 0 or 1 after a median of 12.5 days post-glucarpidase. Glucarpidase was well-tolerated overall; adverse events included paresthesia (2.0%), flushing (1.8%) and headache (1.0%). Eight percent of patients died within 30 days of glucarpidase administration of causes unrelated to glucarpidase, as judged by the treating physician. Conclusions: Glucarpidase is well-tolerated and reduces MTX concentrations by 99% within 15 min of administration in patients with impaired renal clearance of MTX.
Patterns of distant metastases in HPV-positive head and neck squamous cell carcinoma.
Authors: Jennie York Law, Susie Anne Chen, David E. Gerber, Randall S. Hughes, Alejandra Madrigales, Larry L. Myers, Lucien Alexander Nedzi, Baran D. Sumer, John Truelson, John Stuart Yordy, Hong Zhu, Saad A. Khan
Journal: Journal of Clinical Oncology (2014)

6071 Background: Patients with HPV-positive head and neck squamous cell carcinoma (HPV+HNSCC) demonstrate favorable outcomes compared to HPV-negative SCC. Despite loco-regional control distant metastases (DM) can occur. The pattern of DM in HPV+HNSCC is not clearly defined. Methods: 109 patients with HPV+HNSCC underwent treatment at our institution from 2010-2012 (HPV status not identified prior to 2010). Recurrence time and metastatic sites were compared to patients with high risk HPV-negative/unknown SCC (HR HPV-/unk) and intermediate risk HPV-negative/unknown SCC (IR HPV-/unk) from 2006-2012. Results: Group 1: 109 patients with HPV+HNSCC (10 never achieved initial disease control). 7/109 (6.4%) developed DM. Median time to metastases was 11 months (range 7-41 months, mean 16 months). Median follow up from diagnosis was 18 months. Predominant sites of metastases were lung (6), liver (1), bone (1), and brain (1). 5/7 patients with DM (out of 65 patients with a tobacco history and 44 without) had prior or current tobacco use. Primary sites of disease were base of tongue (4/49 total base of tongue sites), tonsil (1/27), glottis (1/9), and nasal cavity (1/1). Group 2: 546 high risk HPV-/unk patients (hypopharynx/larynx/glottis). 124 never achieved initial disease control. 25/546 (4.6%) developed DM. Median time to metastases was 15 months (range 6-52 months, mean 18 months). Median follow up was 25 months. Predominant sites of metastases were lung (10), bone (3), and CNS (3). Group 3: 839 intermediate risk HPV-/unk patients (oral cavity/oropharynx/hard palate/tonsil). 246 never achieved initial disease control. 34/839 (4.1%) developed DM. Median time to metastases was 9 months (range 3-54 months, mean 14 months). Median follow up was 24 months. Predominant sites of metastases were the lung (12), bone (2), and liver (2). Conclusions: At median follow up of 18-25 months, there was no difference in the overall rate of DM for HPV+HNSCC compared to HR HPV-/unk (p=0.21) and IR HPV-/unk (p=0.13) but there was a significant difference in the rate of DM to the lung in the HPV+HNSCC group compared to HR HPV-/unk (p=0.012) and IR HPV-/unk (p=0.002). In our data set, HPV+HNSCC showed a higher rate of DM to the lung compared to HPV-/unk HNSCC (p=0.002).
Pharmacokinetic study of oxaliplatin (lohp) and capecitabine combination in advanced colorectal cancer
Authors: M. Gil-Delgado, G. Bastian, B. Paule, S. Urien, J.-P. Spano, G. Deguetz, K. Chouania, P. Saintini, J.-L. Breau, D. Khayat
Journal: Journal of Clinical Oncology (2004)

2108 Purpose: This trial has been designed in order to establish potential pharmacokinetic (PK) interaction between Oxaliplatin (Oxa)and Xeloda (Xel) when administrated in combination and to monitor neurological toxicity when Oxa is administered over 6 hours infusion. Treatment schedule: Oxa 130 mg/m2 6 hours perfusion at day 1, Xel 1000 mg/m2 twice daily at day 2 to 15. Treatment repeated every 22 days if > 1000 neutrophiles and > 100 000 platelets and no other G 3–4 non hematological toxicity. PK analysis were performed at day 1 and 15; receptor for IL 6 at day 1. Blood sampling was done - on day 1 (30min before the end of infusion and 1h30min after the end of infusion in order to validate the Pk population model we recently published for Oxa). On day 2, 30min, 1h, 2h and 4h after Xel. Xel, dFdC, dFdU, 5FU and FBAL were monitored by HPLC and GC-MS in order to determine potential metabolic interaction with Oxa. On day 14, 30min, 1h, 2h and 4h after Xel in order to compare adsorption and PK of Xel and metabolites with and without Oxa. Results: Between April 2003, and December 2003, 10 patients with advanced colo-rectal cancer were included, in first line chemotherapy for metastatic disease, 3 males and 7 females, 7 colon cancer and 3 rectum, medium age 56 (46 to 66) : PS 0=7, PS 1=2, PS 2=1; liver involvement in 8 patients (80 %) and lung in 4 patients (40 %); median cycles 4 (1 to 9). Toxicity = 3 pts Grade III diarrhea, 1 heart pain at day 2 of first cycle and 1 unexplained death. No hand-food syndrome was observed in this population. Only mild paresthesia in 2 Pts (20%)after 7 cycles Efficacy : 2 CR, 2 PR and 2 stabilizations. PK and IL6 receptor results will be presented. So far, 2 plasma samples are enough to extrapolate AUC of ultrafilterable Oxa according our model. Pk of Xel and metabolites are currently evaluated and Pk interaction between Oxa and Xel will be analysed. Conclusion: This combination is active, easy to administer and very well tolerated especially without significant neurological toxicity when Oxa is infused over 6 hours. Moreover, 2 blood samples are sufficient to monitor Oxa Pk according to the population Oxa parameters and to consider posology adaptation in further trials. No significant financial relationships to disclose.
The Voice of Surrogate Decision-Makers. Family Responses to Prognostic Information in Chronic Critical Illness
Authors: Judith E. Nelson, Laura C. Hanson, Kristine L. Keller, Shannon S. Carson, Christopher E. Cox, James A. Tulsky, Douglas B. White, Emily J. Chai, Stefanie P. Weiss, Marion Danis
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Information from clinicians about the expected course of the patient's illness is relevant and important for decision-making by surrogates for chronically critically ill patients on mechanical ventilation.To observe how surrogates of chronically critically ill patients respond to information about prognosis from palliative care clinicians.This was a qualitative analysis of a consecutive sample of audio-recorded meetings from a larger, multisite, randomized trial of structured informational and supportive meetings led by a palliative care physician and nurse practitioner for surrogates of patients in medical intensive care units with chronic critical illness (i.e., adults mechanically ventilated for ≥7 days and expected to remain ventilated and survive for ≥72 h).A total of 66 audio-recorded meetings involving 51 intervention group surrogates for 43 patients were analyzed using grounded theory. Six main categories of surrogate responses to prognostic information were identified: (1) receptivity, (2) deflection/rejection, (3) emotion, (4) characterization of patient, (5) consideration of surrogate role, and (6) mobilization of support. Surrogates responded in multiple and even antithetical ways, within and across meetings.Prognostic disclosure by skilled clinician communicators evokes a repertoire of responses from surrogates for the chronically critically ill. Recognition of these response patterns may help all clinicians better communicate their support to patients and families facing chronic critical illness and inform interventions to support surrogate decision-makers in intensive care units. Clinical trial registered with www.clinicaltrials.gov (NCT 01230099).
A phase II nonrandomized trial of sequential chemoradiation (gemcitabine/carboplatin plus thoracic irradiation) in patients with unresectable stage III non-small cell lung cancer (NSCLC)
Authors: E. Hamada
Journal: Journal of Clinical Oncology (2004)

7252 Background: The primary objective of this phase II, prospective, nonrandomized study was to determine the overall response rate in previously untreated patients with locally advanced unresectable stage III NSCLC after treatment with sequential chemoradiation (gemcitabine/carboplatin plus thoracic irradiation). The secondary objectives were to determine toxicity, median survival, and progression-free survival. Methods: Chemonaive patients with histological or cytological diagnosis of stage III unresectable NSCLC received gemcitabine 1 gm/m2 infusion over 30 minutes on days 1 and 8 and carboplatin AUC 5 infusion over 1 hour on day 1 after the gemcitabine infusion. Both drugs were given in a 21-day cycle for a maximum of 4 cycles. Patients achieving complete remission (CR), partial remission (PR), or stable disease (SD) after 4 cycles were given external beam irradiation 56–60 Gy to the primary site and mediastinum. All patients had WHO performance status of 0–2, adequate bone marrow, liver, and kidney functions, and life expectancy of more than 6 months. Results: From December 2001 to June 2003, 45 patients were enrolled at NEMROCK and Agouza hospital. The median age was 48 years (range, 28–68 years). All 45 patients were evaluable for response and toxicity. Among them, 4 (8.9%) patients achieved CR and 17 (37.7%) patients achieved PR for an overall response rate of 46.6% (95% CI, 22.7%–59.7%); 16 (35.5%) patients had SD and 8 (17.7%) patients had progressive disease. The median duration of response was 6 months, median time to progression was 8 months, and median survival was 11 months. The predominant toxicity was hematological, with grade 3/4 leukopenia occurring in 14 (31.1%) patients. Conclusions: Sequential chemoradiation (gemcitabine/carboplatin plus thoracic irradiation) is an effective and well-tolerated treatment for advanced, unresectable, stage III NSCLC. No significant financial relationships to disclose.
Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia
Authors: Kenneth F. Bradstock, Emma Link, Juliana Di Iulio, Jeff Szer, Paula Marlton, Andrew H. Wei, Arno Enno, Anthony Schwarer, Ian D. Lewis, James D’Rozario, Luke Coyle, Gavin Cull, Phillip Campbell, Michael F. Leahy, Uwe Hahn, Paul Cannell, Campbell Tiley, Ray M. Lowenthal, John Moore, Kimberly Cartwright, Ilona Cunningham, John Taper, Andrew Grigg, Andrew W. Roberts, Warwick Benson, Mark Hertzberg, Sandra Deveridge, Philip Rowlings, Anthony K. Mills, Devinder Gill, Peter Bardy, Lynda Campbell, John F. Seymour
Journal: Journal of Clinical Oncology (2017)

Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m 2 daily for 5 days, etoposide 75 mg/m 2 daily for 5 days, and idarubicin 9 mg/m 2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P &lt; .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.