tbuckley/cabot-search huggingface dataset:
Risk of thromboembolism associated with an angiogenesis inhibitor bevacizumab in cancer patients
Authors: D. T. Chu, S. R. Nalluri, S. Wu
Journal: Journal of Clinical Oncology (2008)

14559 Background: Bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF), is widely used in the treatment of many solid tumors. Many clinical studies have reported that bevacizumab is associated with thromboembolic events. However, the overall risk of thromboembolism is not known for patients receiving bevacizumab treatment. We performed a systematic review and meta-analysis of published clinical trials to assess the risk of thromboembolism associated with its use. Methods: Databases from MEDLINE (Ovid 1966–2007), the Web of Science, and abstracts presented at American Society of Clinical Oncology annual meetings from 2004 through 2007 were searched to identify relevant studies. Eligible studies included prospective randomized controlled clinical trials in which a standard chemotherapeutic agent was employed with and without bevacizumab the data for thromboembolism available. The summary incidence rate, relative risk (RR), and 95% confidence interval (CI) were calculated using the random-effects or fixed-effects model depending on the homogeneity of studies. Results: A total of 4,080 patients with metastatic colorectal, non-small cell lung, breast, renal cell cancer or malignant mesothelioma from nine clinical trials were identified and included for analysis. Among those patients receiving bevacizumab, the summary incidence of thromboembolism was 14.1% (95% CI: 12.5–15.9%). Patients treated with bevacizumab had a significant increased risk of thromboembolism with RR of 1.45 (95% CI: 1.19–1.76, P < 0.001) when compared to controls. The risk appears dose-dependent, with significant risk associated with the administration of bevacizumab at high dose (10 or 15 mg/kg/dose) (RR 1.69, 95% CI: 1.20–2.37, P = 0.002) but not low dose (5 or 7.5 mg/kg/dose) (RR 1.21, 95% CI: 0.93–1.56, P = 0.14). Interestingly, there is no significant risk of pulmonary embolism associated with bevacizumab (RR 0.80, 95% CI: 0.45–1.42, P = 0.44). Conclusions: There is a significant increased risk of developing thromboembolism but not pulmonary embolism in cancer patients receiving bevacizumab. Further studies are recommended to study the prevention of thromboembolism in patients receiving high dose bevacizumab. No significant financial relationships to disclose.
A comparative analysis of inpatient Do Not Resuscitate (DNR) forms used at National Cancer Institute-designated cancer centers (NCICC)
Authors: D. S. Zhukovsky, J. P. Hwang, J. L. Palmer, M. Smith, A. Flamm, J. Willey
Journal: Journal of Clinical Oncology (2004)

8222 Background: The decision-making process establishing inpatient DNR status is difficult and may lead to conflict among the patient, family and clinician. In this study, we examined DNR forms from NCICC to determine content and process. Our goal was to summarize the range of currently accepted practice and frequency of specific components of inpatient DNR orders at NCICC in the U.S. Methods: Letters were mailed to NCICCs inviting participation in this IRB approved study, with repeat mailing at 4 weeks and follow up phone calls at 8 weeks. Stamped envelopes were provided for return of inpatient DNR order forms. 2 physicians (MD) evaluated each form for content and components of the process used to establish DNR. Descriptive analysis was performed using SAS. Results: 34/50 (68%) eligible sites responded and 30 (60%) participated. 67% of the participating sites used specific inpatient DNR forms; the remainder established DNR status exclusively by order sheets and without forms. 70% of form titles were negative in connotation, 30% neutral and none were favorable. 30% provided a definition of cardiopulmonary resuscitation or of DNR. 57% were confined exclusively to resuscitation efforts, with the remainder offering additional levels of treatment limitation. The majority of forms were indefinite in duration, with 20% time-limited. 25% specified exceptions for the operating room and 10% contained references to minors. Requirement for MD signature was universal, with 25% each also requiring patient and/or surrogate signatures. Additional requirements included documentation of persons involved in the decision (20%) and content of DNR discussion (67%). Conclusions: There is a wide range of practice in establishing DNR status at NCICC. Institutions were almost equally divided between addressing resuscitation exclusively versus resuscitation with limitation of other supportive therapies. Documentation of patient participation in the process is uncommon. A more consistent approach to addressing appropriate care options at the end of life could potentially facilitate decision making around this sensitive issue. No significant financial relationships to disclose.
A Simon 2 stage study of 5,10 methylenetetrahydrofolic acid (CO) with 5-fluorouracil (FU) as first line treatment in metastatic colorectal cancer (mCRC)
Authors: T. R. Reid, C. P. Spears, R. Quadro, M. Subramanian, L. Pawl, G. Jankovic, S. Jelic, N. Milini, L. Muzikravic
Journal: Journal of Clinical Oncology (2005)

3692 Background: We are conducting an open label, Simon 2 stage study to assess the safety and efficacy of CO+FU for first line treatment in mCRC. Unlike leucovorin (LV), CO directly modulates FU inhibition of thymidine synthase without the need for metabolic conversion. Preclinical models show reduced hematologic toxicity of CO+FU with enhanced efficacy compared to FU+LV. Methods: Eligible patients (pts), age ≥18 with ECOG 0–2 and measurable mCRC, w/wo adjuvant FU+LV, irinotecan, or oxaliplatin, but no prior chemotherapy for mCRC. Pts received ≥2 cycles each consisting of CO 60mg/m2 and FU 450mg/m2 (weekly IV bolus) for 6 weeks, followed by 14 day rest. Pre-established response criteria is ≥4 of 23 for stage 1, ≥12 of 48 for stage 2. Response is defined as complete response (CR, complete disappearance), partial response (PR, ≥50% reduction in total tumor size), stable disease (SD, ≤50% reduction), progressive disease (PD, ≥25% increase) at week 16. Results: Safety data is available for 30 pts, median age 65.5 (range 42–86), F=53.3%, mean number of doses 10.2 (range 1–24). Overall incidence of grade 3/4 AEs was 2(6.6%, bowel obstruction, malignant pleural effusion). No grade 3/4 blood toxicity was observed. Response data is available for 12 pts: 3 PR, 6 SD, 3 PD. Conclusions: CO+FU has been well tolerated. The remaining pts are expected to be enrolled and data will be reported at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Adventrx Adventrx
A single center review of the experience with mitomycin C (MMC) and the risk of thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS)
Authors: C. E. Arce-Lara, S. Cataland, C. Brady, E. Kraut, G. Otterson, M. Villalona-Calero, T. Bekaii-Saab
Journal: Journal of Clinical Oncology (2007)

15167 Background: MMC related TTP/HUS has been reported between 4 and 15%, with a higher incidence in patients receiving cumulative doses of 60 mg or higher. It tends to occur within 4 months of drug administration independently of patients’ cancer status. The ability of MMC to upregulate enzymes relevant for new cytototoxic agents (topoisomerase I for CPT-11 and thymidine phosphorylase for capecitabine) make phamacobiologically based therapeutic combinations including MMC attractive. Methods: All patients (n=100) that participated in four institutional clinical studies from 2000 through 2004 were included. The studies were OSU 9947 (phase I trial of CPT-11 and MMC in solid tumors, n=31) OSU 0151 (phase II trial of CPT-11 and MMC in advanced esophageal and stomach cancer, n=41) OSU 0155 (phase II trial of CPT-11 and MMC in patients with refractory breast cancer, n=26) OSU 0330 (phase I study of capecitabine and MMC in patients with advanced GI tumors n=2). In each study, the maximum cumulative dose of MMC was 36 mg/m 2 . All patients were followed for clinical signs or symptoms of TTP/HUS including the presence of anemia, thrombocytopenia and renal insufficiency and had a thorough review of the peripheral smear. Results: The median cumulative dose was 12 mg/m 2 (range 3–36 mg/m 2 ). No patients met the clinical diagnosis of TTP/HUS except for one patient had anemia, thrombocytopenia and renal insufficiency but did not manifest any other findings consistent with TTP/HUS such as changes in mental status, azotemia or any other clinical symptom. The laboratory abnormalities resolved without intervention within seven days with subsequent continuation on the clinical trial. Conclusions: In this study we have demonstrated that by capping the cumulative dose of MMC to 36 mg/m 2 , the incidence of TTP/HUS is minimal. Furthermore, our preliminary analysis of an additional 100 patients treated with MMC at OSU shows no reported cases of TTP/HUS (additional data will be presented at the meeting). Since MMC is effective in a wide variety of solid tumors including breast, lung and GI malignancies and is inexpensive and easy to administer, further exploration of MMC in the treatment of solid malignancies is indicated including rational combination studies. No significant financial relationships to disclose.
Perspectives on the financial burden of cancer care: Concurrent surveys of patients (Pts), caregivers (CGs), and oncology social workers (OSWs).
Authors: M. Eichholz, J. Pevar, T. Bernthal
Journal: Journal of Clinical Oncology (2010)

9111 Background: In the United States, cancer treatment is often associated with substantial financial burden. To better understand the financial issues associated with cancer and their impact on Pts, concurrent surveys of Pts, CGs, and OSWs were undertaken in a collaborative effort between Kelton Research and the Association of Oncology Social Work (AOSW), funded by Millennium pharmaceuticals. Methods: Pts and CGs recruited from 2 national research panels and AOSW members were invited to complete online surveys in Oct–Nov 2009; 169 Pts, 131 CGs, and 153 OSWs responded. Pt/CG data are presented in aggregate. Results: 57% of Pts had experienced serious hardship relating to bills for cancer treatment, including depleted savings (40%) and bankruptcy (6%). 39% of Pts had a serious or catastrophic financial burden; among these Pts, costs negatively impacted ability to focus on recovery in 87%, and 75% constantly worried about financial issues. 51% of CGs tried to shield Pts from the financial aspects of treatment, while 73% of OSWs reported discussing financial issues with all/most of their Pts and 58% indicated this always or frequently had a positive result. While 62% of Pts indicated they were familiar with the treatment options covered by their health plan, OSWs perceived that only 4% of Pts with newly diagnosed cancer are aware of their options. OSWs witnessed the impact of financial issues on Pt adherence to treatment (Table). Although 69% of OSWs perceived themselves to be their Pts' primary resource for dealing with financial issues associated with cancer treatment, only 34% of Pts/CGs reported interacting with an OSW. Conclusions: The financial challenges of treatment are a key issue facing pts with cancer, which can interfere with treatment protocols and impact adherence. OSWs can support pts in working through financial and psychosocial barriers to treatment and enhanced quality of life, yet only a third of Pts report interacting with an OSW. Compliance issue OSWs witnessing, % Delay/failure to fill prescription 88 Asking for less expensive treatment 66 Skipped appointment to avoid co-pay 64 Skipped dose 58 Cut dose in half 58 Did not get/postponed treatment 56 Ended treatment early 52 No significant financial relationships to disclose.
Evaluation of plectin-1 immunohistochemical expression in human colon cancer tumor progression
Authors: G. J. Kannarkat, T. Harris, K. Kelly, P. Fracasso, C. Moskaluk
Journal: Journal of Clinical Oncology (2009)

e22132 Background: Plectin-1 (PLEC1), a known scaffolding protein, was recently discovered to be upregulated and redistributed to the cell membrane in multiple cancers, thereby providing a molecular imaging biomarker for disease detection. The purpose of this study was to examine PLEC1 staining in the tumor progression of human colorectal carcinoma. Methods: A tissue microarray of colonic neoplastic progression was stained with antibody to PLEC1. A total PLEC1 immunohistochemical (IHC) staining score was obtained by multiplying the intensity of PLEC1 membrane staining, scored 1 to 3, by the percent of target cells stained, scored 1 (&lt;25%), 2 ( 25%-75%) and 3 (&gt;75%). Each specimen was grouped into low (0–2), intermediate (3–5) or high (6–9) expression. The mean IHC score and group distribution were obtained for each tissue type. Results: Normal colonic tissue showed the lowest membrane expression of PLEC1 with a mean IHC score of 2.24. Approximately 80% of cases were in the low group. Colonic adenomas had a slightly higher mean IHC score, 2.57, with more cases falling in the intermediate group. Invasive colorectal cancer as a whole had a mean IHC score of 3.96 with a third of cases falling into the high expression group. Inflamed colonic tissue (ulcerative colitis) stained the highest with a mean IHC score of 4.83 and all cases falling in the intermediate or high group. Conclusions: There is increasing membrane expression of PLEC1 in colonic epithelium through tumor progression. The observation of a difference in IHC staining of normal and malignant tissue requires larger confirmatory studies, but the redistribution of PLEC1 to the cell surface is a potential biomarker for molecular imaging of cancer and potential target for novel therapeutic agents. However, our finding of increased PLEC1 membrane staining in actively inflamed tissue may indicate an important caveat in the use and implementation of this biomarker in certain clinical situations. [Table: see text] No significant financial relationships to disclose.
Elevated serum M-CSF level predicts reduced survival in metastatic breast cancer patients
Authors: K. Leitzel, S. Ettenberg, R. Walsh, J. Abraham, V. Modur, E. Braendle, D. B. Evans, S. M. Ali, L. Demers, A. Lipton
Journal: Journal of Clinical Oncology (2007)

10591 Background: Macrophage colony stimulating factor (M-CSF) and its receptor (CSF-1R, the c-fms oncogene protein product) have been reported to be expressed in a variety of cancers, including breast cancer. The M-CSF produced by breast cancer cells and surrounding stromal cells increases osteoclast formation and maturation and enhances the expression of stromal RANK ligand, both of which increase osteolytic bone degradation. In this study we evaluated the predictive and prognostic potential of circulating M-CSF in metastatic breast cancer patients treated with hormone therapy. Methods: Using an M-CSF ELISA (R&amp;D Systems, Minneapolis, MN), M-CSF concentration was determined in pretreatment sera from 204 metastatic breast cancer patients enrolled in a phase III 2 nd -line hormone therapy trial of fadrozole vs. megace, and also in sera from 25 post-menopausal control female subjects. Results: The serum M-CSF level from the 25 healthy post-menopausal female control subjects had a mean ± SD of 835.6 ± 276.1 pg/ml (range 319.0 - 1,465.8 pg/ml). The upper limit of normal was defined as the 95 th percentile of the serum M-CSF level from the female control group (1277 pg/ml). Pretreatment serum M-CSF levels from the metastatic breast cancer patients ranged from 82.2 - 3,019.8 pg/ml, and were found elevated above the upper limit of normal in 15 of 204 patients (7.35 %). Patients with elevated pretreatment serum M- CSF did not have a significantly different objective response rate, clinical benefit rate, or time to progression to hormone therapy; but these patients did have significantly reduced overall survival (median survival 10.0 months) compared to patients with normal serum M-CSF levels (median survival 24.3 months)(p = 0.007). In multivariate analysis with serum HER-2/neu included as a covariate, elevated serum M-CSF level remained a significant independent variable for reduced survival (p= 0.032). Conclusions: Pretreatment serum M-CSF levels were elevated in 7 % of metastatic breast cancer patients compared to healthy female control subjects, and these patients had significantly reduced overall survival. Serum M-CSF deserves further study to determine its predictive and prognostic biomarker potential in breast cancer patients. No significant financial relationships to disclose.
Genome-wide association study (GWAS) of the efficacy of capecitabine, oxaliplatin, and bevacizumab in metastatic colorectal cancer in the CAIRO2 trial of the Dutch Colorectal Cancer Group (DCCG).
Authors: H. Guchelaar, J. Pander, S. Bohringer, T. van der Straaten, Y. Ariyurek, J. Houwing-Duistermaat, H. Gelderblom, C. J. A. Punt
Journal: Journal of Clinical Oncology (2011)

3609 Background: A more optimal selection of patients that will benefit from the frequently used first-line treatment of advanced colorectal cancer (ACC) consisting of the combination of capecitabine, oxaliplatin and bevacizumab (CAPOX-B) is warranted. We used a GWAS to find single nucleotide polymorphisms (SNPs) that are associated with the efficacy of CAPOX-B. This is the first pharmacogenetic GWAS with progression-free survival (PFS) as an endpoint. Methods: Germline DNA was obtained from 547 previously untreated ACC patients in the randomized phase III CAIRO2 trial of the DCCG, in which patients were randomized between CAPOX-B or CAPOX-B plus cetuximab. Whole-genome genotyping was performed using 700 k Illumina OmniExpress BeadChip arrays. Associations between SNPs and PFS were tested using Cox-proportional hazard models. Associations were considered significant when P < 5 x 10-8. Results: Three SNPs located at 8p23.1 showed a trend toward significance for association with PFS (rs292936519, P = 1.24 x 10-7; rs2912024, P = 1.38 x 10-7 and rs2978931, P = 6.75 x 10-7). These SNPs are 20 kbp downstream of the AGPAT5 gene. The AGPAT5 gene encodes a protein that converts lysophosphatidic acid (LPA) to phosphatidic acid (PA), the second step in de novo phospholipid biosynthesis, the major constituent of the cell-membrane. Additionally, LPA is a potent mitogen that has been linked to the development and progression of breast cancer. There was significant interaction between treatment arm and the rs885036 SNP in the MGAT4A gene (P = 4.16 x 10-8). Conclusions: Our results suggest that genetic variation in the AGPAT5 gene is associated with the efficacy of CAPOX-B. Validation is required before definitive conclusions can be made based upon these data.
Phase I trial of intratumoral administration of OBP-301, a novel telomerase-specific oncolytic virus, in patients with advanced solid cancer: Evaluation of biodistribution and immune response
Authors: T. Fujiwara, N. Tanaka, J. J. Nemunaitis, N. N. Senzer, A. Tong, D. Ichimaru, S. M. Shelby, Y. Hashimoto, H. Kawamura, Y. Urata
Journal: Journal of Clinical Oncology (2008)

3572 Background: Telomerase activation is considered to be a critical step in carcinogenesis and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We constructed an adenovirus 5 vector (OBP-301 [Telomelysin]), in which the hTERT promoter drives expression of E1A and E1B genes linked with an IRES. OBP-301 causes selective replication and lysis of a variety of human cancer cells, and has shown preclinical efficacy against human tumor xenografts. A phase I study was designed to determine the feasibility and to characterize the pharmacokinetics of OBP-301 in patients with advanced solid tumors. Methods: Patients with histologically confirmed advanced solid tumors were enrolled into this phase I trial. Nine patients received escalating dose levels of OBP-301 (1 x 1010 to 1 x 1012 virus particles [vp]) as monotherapy. Patients were monitored over two months for safety and tolerability, vector distribution, antibody formation, and tumor response. Virus shedding was monitored in the saliva, sputum, urine, and plasma by a quantitative DNA-PCR assay targeting the IRES sequence. Results: All patients received a single intratumoral injection of OBP-301 without dose-limiting toxicity. The primary tumor types were head and neck (n=2), breast (n=1), soft tissue (n=1), and others (n=5). Circulating OBP-301 viral genome became detectable in the plasma within 24 hours after injection in all patients except one. This dose-dependent initial peak in circulating virus was followed by a rapid decline; however, two patients received 1010 and 1012 vp showed a second peak of circulating viral DNA on day 14, suggesting OBP-301 replication in primary tumors. In contrast, no viral DNA was detected in all saliva, sputum, and urine samples except two specimens. Titers of neutralizing antibody to adenovirus collected at 28 days after injection of OBP-301 were higher than the titers at baseline in all 8 patients tested. All patients had stable disease at the day 28 assessment, although 6 patients showed 6.6 to 34% tumor size reduction. Conclusions: OBP-301 is well-tolerated and warrants further clinical studies for solid cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Oncolys BioPharma, Inc. Oncolys BioPharma, Inc. Oncolys BioPharma, Inc.
Vandetanib In Locally Advanced Or Metastatic Differentiated Thyroid Cancer (Papillary Or Follicular; Dtc): A Randomized, Double-Blind Phase Ii Trial
Authors: S. Leboulleux, L. Bastholt, T. M. Krause, C. De La Fouchardiere, Jan Tennvall, A. Awada, J. M. Gomez, A. Tisseron Carrasco, M. Licour, M. J. Schlumberger
Journal: Annals of Oncology (2010)