tbuckley/cabot-search huggingface dataset:
Effect of bevacizumab (Bev) on the growth rate constants of renal carcinoma (RCC) tumors
Authors: A. T. Fojo, W. D. Stein, J. Yang, S. E. Bates
Journal: Journal of Clinical Oncology (2008)

11044 Background: An analysis of the phase II bevacizumab versus placebo trial using a novel algorithm suggests the lack of a overall survival (OS) advantage for bevacizumab may have been a result of early discontinuation of therapy. To hasten cancer drug development, new paradigms, especially ones applicable to pts with metastatic disease, are needed to assess therapeutic efficacy. In a randomized phase II study in pts with RCC, 10 mcg/kg Bev every 2 weeks prolonged time to progression but a statistically significant improvement in OS could not be demonstrated. Methods: We describe a novel method to assess therapeutic efficacy using tumor measurements gathered while a patient receives therapy in a clinical trial. We developed and validated a two-phase equation to estimate concomitant rates of tumor regression (regression rate constant, d) and tumor growth (growth rate constant, g). Results: For pts on placebo, the mean g value was 10-2.231 day-1 compared to a value of 10-2.561 day-1 for pts on 10 mcg/kg Bev (p < 0.001) and in all pts g correlated with OS. By comparison, the differences in d were not statistically significant and although the regression portion of the curve was needed to accurately describe the data, it did not predict OS in these pts with RCC. A log difference of 0.330 in mean g between placebo and 10 mcg/kg Bev could have translated into at least 386 ± 81 days of added OS, not the observed 47 days. That a OS advantage was not demonstrated with Bev appears to have been a result of early discontinuation of Bev. Conclusions: Single agent Bev significantly affects the growth rate constants of RCC and, in pts with metastatic disease, will likely impact OS if continued beyond standard criteria for progressive disease. The mathematical model described herein has applications to many tumor types and should aid in evaluating relative efficacies of different therapies. Modeling tumor progression using data gathered while patients are enrolled on a clinical trial as has been done in the present study may streamline drug development and accelerate drug approval. Consideration should be given to study designs that include an experimental arm in which pts continue therapy despite disease progression beyond arbitrary endpoints. No significant financial relationships to disclose.
Use of complementary/alternative medicine by Brazilian oncologists
Authors: E. S. Tibana Samano, A. Del Giglio, L. M. Ribeiro, A. S. Campos, F. Lewin, E. S. Valesin Filho, P. T. Goldenstein, L. J. M. Costa
Journal: Journal of Clinical Oncology (2004)

8196 \(\underline{\mathrm{Background}}\): Complementary and alternative medicine (CAM) is defined as “drugs or therapeutic methods that are not included in the accepted orthodox biomedical framework of care for cancer patients” (Paltiel, J Clin Oncol 2001;19(9):2439–2448). We conducted an extensive survey among Brazilian cancer physicians to understand their attitude toward CAM. Methods: We sent a questionnaire to all the 657 members of Brazillian Cancer Society addressing their knowledge and attitudes concerning CAM, whether they used to ask their patients about their use of CAM, which were the various practices of CAM known by these doctors and the possible reasons that lead them to indicate or not CAM to their patients. We also questioned them regarding their degree of awareness of CAM self administration by their patients. Results: Overall 119 questionnaires were returned to us (18%). Most oncologists knew at least one type of CAM (115 or 96.6%) and 76.7% had previously made use of at least one type of CAM for themselves (individual prayers - 46.2%, vitamin supplements - 35.3%, psychotherapy - 29.4%, massage - 26%, group prayers - 24.4% and acupuncture - 24.4%) We observed that 63.8% (CI95%; 55.1–72.5) of the oncologists used to ask their patients about CAM utilization and 37.8% described at least one reason to stimulate its use (68.8% as complementary treatment). Ninety-six physicians (80.7%; CI95;73.6%–87.8%), described at least one reason to not indicate CAM, mainly, 56.2% (CI95 55.8%–56.6%) for lack of scientific proof of efficacy. Most oncologists (90%) would prescribe at least one type of CAM and this attitude correlated significantly with previous physicians' use of CAM (p=0.0001) and with being a clinical oncologist as well as with having questioned patients about CAM use (p=0.002). \(&lt;F&gt;\underline{\mathrm{\mathrm{Conclusions}}}&lt;/F&gt;\): Brazilian oncologists know many kinds of CAM, had themselves frequently used some type of CAM and most of them would indicate some type of CAM to their patients. Therefore, the frequent use of CAM by Brazilian cancer patients seems to be supported by their physicians. No significant financial relationships to disclose.
A phase Ib/II study evaluating activity and tolerability of BTK inhibitor PCI-32765 and ofatumumab in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and related diseases.
Authors: Samantha Mary Jaglowski, Jeffrey Alan Jones, Joseph M. Flynn, Leslie A. Andritsos, Kami J. Maddocks, Kristie A. Blum, Michael R. Grever, Susan Michelle Geyer, Jennifer Ann Woyach, Amy J Johnson, Nyla A. Heerema, Erin Molnar, Mona Stefanos, Susan Devlin, Tasheda Navarro, Danelle Frances James, Ann M. Lowe, Eric Hedrick, John C. Byrd
Journal: Journal of Clinical Oncology (2012)

6508 Background: Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that is critical for B-cell receptor (BCR) signaling in normal and malignant B lymphocytes. PCI-32765 (P), an oral, potent and irreversible BTK inhibitor, antagonizes BCR signaling in CLL cells and abrogates protective features of the microenvironment. P is highly active as a single agent in CLL/SLL patients (pts), and this phase Ib/II study builds upon single-agent experience by combining P with ofatumumab (O), an anti-CD20 monoclonal antibody. We present initial safety and efficacy data from cohort 1. Methods: Pts with relapsed/refractory (R/R) CLL/SLL following ≥2 prior therapies (Tx), including a purine-nucleoside analog (PA), are treated with 420 mg P daily, in 28-day cycles, until disease progression. O is added at a dose of 300 mg on day (D) 1 of cycle 2, followed by 2000 mg on D8, 15, and 22 of cycle 2, D1, 8, 15, and 22 of cycle 3, and on D1 of cycles 5-8. Results: As of November 2011, 27 patients with either CLL/SLL/PLL (n=24) or Richter’s transformation (RT, n=3) have been enrolled and have received at least 6 cycles of treatment. The median age is 66 (range 51-85), 9 were Rai stage III/IV. Median number of prior Tx is 3 (range 2-10), 15 pts had bulky disease (&gt; 5 cm); 11 pts were PA refractory. Poor-risk molecular features were common (del(17p) 10 pts, del(11q) 9 pts). No grade (G) 3 or 4 infusion reactions, neutropenia, or thrombocytopenia have been observed. The majority of adverse events (AE) were G1/2. G3/4 AE included anemia (11%), pneumonia (11%), UTI (7%), hyponatremia (7%). 24/24 CLL/SLL/PLL pts have achieved PR (100% ORR) within 6 cycles; 2/3 RT pts had PR. With median follow-up of 6.5 mo (range 5.3-10.2 mo), 23 CLL/SLL/PLL pts and 1 RT pt remain on study; 1 CLL/SLL pt went to transplant in PR; 2 RT pts progressed. Conclusions: PCI-32765 combined with ofatumumab is well tolerated and highly active (100% ORR) in pts with heavily pre-treated R/R CLL/SLL. Rapid onset of response, low relapse rate, and favorable safety profile make this combination worthy of further study. Cohorts evaluating other Tx sequences are currently underway.
A randomized trial of prophylactic cranial irradiation (PCI) versus no PCI in extensive disease small cell lung cancer after a response to chemotherapy (EORTC 08993–22993)
Authors: B. Slotman, C. Faivre-Finn, G. Kramer, E. Rankin, M. Snee, M. Hatton, G. de Schaetzen, L. Collette, S. Senan
Journal: Journal of Clinical Oncology (2007)

4 Background: Prophylactic cranial irradiation (PCI) significantly reduces the risk of brain metastases (BM) and improves survival in patients with limited disease small cell lung cancer. Development of BM is often accompanied by deterioration of physical and psychological functioning and response to therapy is poor. Patients with extensive disease (ED SCLC) are at high risk for BM. This randomized study assesses PCI in patients with ED SCLC. Methods: Patients (18–75 years; WHO=2) with confirmed ED SCLC and any response to 4–6 cycles of chemotherapy, were randomized to receive PCI (doses ranging from 20 Gy/5 fr to 30 Gy/12 fr) or no PCI. The primary endpoint was the cumulative incidence of symptomatic BM. CT or MRI of the brain was performed whenever any of the pre-defined “key-symptoms” was present at baseline or during follow-up. The study was sized to detect a hazard ratio of 0.44 with 80% power and 2-sided 5% significance (52 events, 287 patients). Results: Between Feb ’01 and Mar ’06, 286 patients entered the trial, 76% with residual disease in the thorax and 71% at distant sites. Baseline characteristics were well balanced. Only 6% of patients in the PCI arm were not treated and 3% interrupted treatment. Acute toxicity was mild: nausea/vomiting was reported by about 30% of PCI-treated cases and about 30% reported late reactions (mostly mild headache). PCI significantly reduced the risk of symptomatic brain metastases (Gray P&lt;0.0001, HR=0.27, CI: 0.16–0.44). The 1-year cumulative incidence of symptomatic BM was 14.6% on PCI (CI 8.3–20.9) versus 40.4% in controls (CI 32.1–48.6). PCI had no impact on extra-cranial progression rates (Gray P&gt;0.1), but it significantly prolonged progression-free survival time (P=0.0218, HR=0.76, CI: 0.59–0.96) and overall survival (P=0.0033, HR=0.68, CI: 0.52–0.88). The 1-year survival rate was 27.1% for the PCI and 13.3% for the control arm. Conclusions: PCI significantly reduces the risk of symptomatic brain metastases, and significantly improves both disease-free and overall survival in patients with ED SCLC. PCI should be offered to all ED patients showing a response to initial chemotherapy. No significant financial relationships to disclose.
Prospective Analysis of Staphylococcus aureus Bacteremia in Nonneutropenic Adults With Malignancy
Authors: Ajay K. Gopal, Vance G. Fowler, Manish Shah, Diane Gesty-Palmer, Kieren A. Marr, R. Scott McClelland, Li Kuo Kong, Geoffrey S. Gottlieb, Kevin Lanclos, Jennifer Li, Daniel J. Sexton, G. Ralph Corey
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To determine the primary sources and secondary complications of Staphylococcus aureus bacteremia (SAB) in cancer patients, as well as predictors of outcome in cancer patients with SAB. PATIENTS AND METHODS: Fifty-two patients at Duke University Medical Center met entry criteria between September 1994 and December 1996 for this prospective cohort study involving hospitalized nonneutropenic adult cancer patients with SAB. All subjects were observed throughout initial hospitalization and were evaluated again at 6 and 12 weeks or until death. RESULTS: SAB was intravascular device–related in 42%, tissue infection–related (TIR) in 44%, and unidentifiable focus–related (UFR) in 13%. Seventeen patients (33%) were found to have metastatic infections or conditions, with eight (15%) developing infectious endocarditis (IE). Patients with TIR bacteremia were less likely than other patients to develop IE (4% v 24%, P = .06). The overall mortality rate was 38%, the SAB-related mortality rate was 15%, and the rate of SAB relapse was 12%. Methicillin resistance was not associated with adverse outcome. Inability to identify a point of entry (UFR bacteremia), however, was associated with a higher overall mortality rate (100% v 24%, P = .0006). Furthermore, a 72-hour surveillance blood culture positive for organisms was associated with an increased incidence of IE (P = .0006), metastatic infections or conditions (P = .0002), SAB relapse (P = .038), and SAB-related death (P = .038). CONCLUSION: SAB in cancer patients is associated with significant morbidity from frequent metastatic infections or conditions including IE, as well as considerable mortality. Unknown initial infection site and 72-hour surveillance cultures positive for organisms were predictive of a complicated course and poor final outcome.
Phase II exploratory study of brostallicin in patients with ovarian cancer resistant/refractory to platinum-based chemotherapy
Authors: D. Lorusso, F. Zanaboni, S. Scalone, R. Secomandi, G. Ferrandina, G. Scambia, M. G. Jannuzzo, A. Petroccione, S. Comis, F. Raspagliesi
Journal: Journal of Clinical Oncology (2008)

16520
Phase I clinical experience of a targeted TCR-IL2 fusion protein in patients with metastatic malignancies
Authors: G. Pennock, M. Fishman, R. Gonzalez, J. Thompson, B. Huang, S. Tang, P. Rhode, H. Wong
Journal: Journal of Clinical Oncology (2009)

3040 Background: ALT-801 is recombinant human interleukin-2 (IL-2) genetically fused to a single-chain T-cell receptor specific to a peptide antigen of human p53 presented in the context of HLA-A2 positivity. In tumor xenografts in animal models, this fusion protein demonstrated potent and targeted antitumor activity. Methods: A phase I/IIa multicenter clinical study was initiated to assess safety and clinical response of ALT-801 in patients with various metastatic malignancies. Patients screened positively for HLA-A2 and tumors expressed p53 peptide/HLA-A2 complex. In this dose escalation trial, patients received ALT-801 as a daily intravenous infusion for 4 days followed by a 10-day rest period and 4 additional daily doses. Results: Data from three dosing cohorts (0.015, 0.04, and 0.08 mg/kg/dose) indicate that ALT-801 is well-tolerated up to 0.04 mg/kg/dose. The half-life of ALT-801 is 2.5–4 hours per pharmacokinetic analysis, depending on the dose. Even at the 0.015 mg/kg level, there were sufficient concentrations of ALT-801 in the patients’ serum to fully activate cell lytic activity in vitro. Treatment with ALT-801 also led to immune activation in patients as demonstrated by elevated serum IFN-γ levels as well as an increase in IFN-γ-producing immune cells in patients’ blood. Interestingly, serum TNF-α, a major inducer of hypotension in patients receiving high-dose IL-2 treatment, was not induced in patients receiving ALT-801. Evidence of antitumor activity (i.e., stable disease, tumor shrinkage) was observed in some patients after one or two courses of ALT-801. Conclusions: At a dose of 0.04 mg/kg, ALT-801 is a well-tolerated agent that generated a vigorous immune response and demonstrated clinical efficacy in a group of patients with various metastatic malignancies. An expansion cohort of patients is in progress at 0.04 mg/kg. [Table: see text]
SMAD4 Sequestrates HOXA9 to Protect Hematopoietic Stem Cells Against Leukemia Transformation
Authors: Ronan Quere, Göran Karlsson, Falk Hertwig, Marianne Rissler, Beata Lindqvist, Thoas Fioretos, Peter Vandenberghe, Marilyn L. Slovak, Kristian Reckzeh, Jörg Cammenga, Stefan Karlsson
Journal: Blood (2010)
Determination of clinically meaningful change (CMC) for functional assessment of cancer therapy-prostate (FACT-P)
Authors: M. A. Carducci, J. B. Nelson, N. J. Vogelzang, P. Mulani
Journal: Journal of Clinical Oncology (2005)

8077 Background: Determining CMCs that explore the relationships between clinical measures and Quality of Life (QoL) and establishing the smallest magnitude of change in QoL that would reflect change in clinical parameters facilitates interpretation of QoL results. CMCs for the FACT-P have not been determined. Our objective was to ascertain the CMC for FACT-P using data from a phase 3 trial of atrasentan (Xinlay) 10 mg in men with metastatic hormone-refractory prostate cancer. Methods: Cross section comparison of baseline FACT-P scores and baseline Karnofsky score (Kfsky), bone alkaline phosphatase (BALP), hemoglobin (Hb), and lactate dehydrogenase (LDH) was performed using t-tests. Longitudinal comparison of changes in FACT-P scores from baseline to week 12 and time to disease progression (TTP), time to bone pain (TTBP), prostate specific antigen doubling time (PSADT) and survival was conducted using analysis of covariance. CMC’s and effect size were calculated using these analyses as well as the standard errors of mean QoL scores. Results: FACT-P scores were significantly associated with all clinical variables evaluated (Table). CMC ranges for FACT-P scores were computed and are shown in the table below. CMC’s based on the distribution based criteria fell within the range identified by clinical variables, corroborating the CMC for each FACT-P score (Table). Conclusions: This analysis defines CMC’s for the FACT-P in metastatic HRPC patients. A decrease in QoL score greater than the minimum value of the CMC range represents the Minimally Clinically Important Difference for that score. This data can aid in the interpretation of QoL outcome using the FACT-P. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories Abbott Laboratories, Aventis, OSI Abbott Laboratories, AstraZeneca, Lilly Oncology, NCI
XELOX with bevacizumab in elderly patients age 75 or older with metastatic colorectal cancer: Results of a planned interim analysis for multicenter phase II ASCA study.
Authors: Keiichiro Ishibashi, Yoshinori Munemoto, Masaki Matsuoka, Taishi Hata, Michiya Kobayashi, Junichi Hasegawa, Mutsumi Fukunaga, Akinori Takagane, Toshio Otsuji, Yasuhiro Miyake, Michitaka Nagase, Koji Oba, Junichi Sakamoto, Hideyuki Mishima
Journal: Journal of Clinical Oncology (2013)

502 Background: Combination chemotherapy of capecitabine plus oxaliplatin (XELOX) with bevacizumab is commonly used as standard chemotherapy for metastatic colorectal cancer (mCRC). A previous meta-analysis showed that there was no difference between two age groups of &lt;65 years and ≥65 years on overall survival (OS) after treatment with chemotherapy with bevacizumab. However, the safety and efficacy of XELOX with bevacizumab in elderly patients (pts) ≥75 years with mCRC remain unclear. Methods: This study was an open-label multicentre phase II study to evaluate the efficacy and safety of XELOX with bevacizumab in pts ≥75 years with metastatic CRC. The primary objective was to assess progression-free survival (PFS). The secondary endpoints were the safety, response rate (RR), time to treatment-failure (TTF) and OS. Results: 36 pts were enrolled. Pts characteristics were; median age 78 (range 75-86); male/female, 21/15; ECOG performance status 0/1, 30/6; colon/rectum 24/12, creatinine clearance (CCr) 60.2 ml/min (range 32.6-84.6). Median follow-up period was 220 days. RR was 55.6% and median TTF was 209 days. The median PFS and median OS are not reached. Grade 3 or 4 adverse events (AEs) were reported in 22 pts (62.8%). Common grade 3 or 4 AEs were hypertension (11.4%), leukopenia (20.0%), peripheral sensory neuropathy (14.3%), hand foot syndrome (8.6%), and fatigue (8.6%). Examining the relationship between renal function (CCr) and AEs, the incidence of Grade 3 or 4 AEs in the lower CCr group was significantly higher than that in the higher CCr group (61.6% vs. 47.8%; p=0.013); hematological toxicities (87.5% vs. 14.8%; p=0.0003) and non-hematological toxicities (61.5% vs. 11.1%; p=0.018). Conclusions: XELOX with bevacizumab is safely administered in elderly patients ≥75 years. Renal function (CCr) could be a good predictive marker for grade 3 or 4 AEs. Clinical trial information: UMIN000003500.
Increased expression of androgen receptor (AR) and enzymes involved in androgen synthesis in metastatic prostate cancer: Targets for novel personalized therapies
Authors: N. Mitsiades, N. Schultz, B. S. Taylor, H. Hieronymus, J. Satagopan, P. T. Scardino, V. E. Reuter, C. Sander, C. Sawyers, H. I. Scher
Journal: Journal of Clinical Oncology (2009)

5002 Background: Androgen receptor (AR) signaling remains active in castration-resistant prostate cancer (CRPC) despite castrate levels of circulating androgens. This is indicated by continuous expression of androgen-responsive genes and is due to mechanisms that include: increased AR expression; AR mutations allowing promiscuous activation by alternative ligands; and increased intratumoral androgen levels, resulting from in situ steroidogenesis. Methods: Gene expression profiles of 30 normal prostate tissue samples, 131 primary prostate carcinomas (PCas) and 16 metastatic PCas, generated using Affymetrix Exon arrays, were interrogated for levels of 40 mRNAs encoding AR, SHBG, 28 enzymes involved in androgen synthesis and 10 enzymes involved in androgen inactivation. For individual tumors, a transcript was considered to be overexpressed or underexpressed when its levels were &gt;2 SDs higher or lower, respectively, than its average levels in normal tissue. Results: Metastatic PCas expressed higher average transcript levels for AR and several steroidogenic enzymes, including SRD5A1 and SRD5A3, than primary PCas and normal prostate tissue. Expression of SRD5A2, CYP3A4, CYP3A5, and CYP3A7 mRNAs was decreased both in primary and metastatic tumors compared to normal prostate tissue. In analysis involving AR and 28 steroidogenic transcripts in individual tumors, all (16/16) metastatic PCas overexpressed at least one transcript (range: 2–14, median: 5 transcripts) compared to normal tissue, while 100/131 (76%) primary PCas overexpressed at least one transcript (range: 2–16, median: 2). Conclusions: Metastatic PCas overexpress AR and several steroidogenic enzymes, while they express lower levels of the androgen-inactivating enzymes CYP3A4, CYP3A5, and CYP3A7. These data highlight the role of AR and the androgen synthetic pathway as a therapeutic target in CRPC. Novel antiandrogens (MDV3100) and CYP17 inhibitors (abiraterone) are already in clinical trials in CRPC. Overexpression of AR or steroidogenic enzymes may serve as a biomarker (e.g. by detection via RT-PCR in circulating tumor cells) to predict for sensitivity to these agents and guide patient selection for participation in clinical trials. No significant financial relationships to disclose.