tbuckley/cabot-search huggingface dataset:
Trastuzumab and vinorelbine (TV) in early stages of breast cancer
Authors: C. Ferrario, A. Wong, N. Bouganim, T. Gao, R. Aloyz, L. C. Panasci
Journal: Journal of Clinical Oncology (2009)

e11556 Background: HER-2+ breast cancers (BCs) have a higher relapse rate, even for early stages of disease. The combination of trastuzumab and vinorelbine (TV) displays a high degree of synergism both preclinically and in metastatic BC patients that typically tolerate TV remarkably well. Occasionally, patients refuse standard treatment with chemotherapy and trastuzumab because of toxic side effects. In our institution, some of these patients accepted to receive treatment with TV. Methods: We retrospectively collected data on patients with stage I-III BCs, treated with TV as the only chemotherapy regimen. Most patients received TV on a weekly basis (one week off for V every 3–4 weeks) for ∼6 months, followed by 6 more months of T only. Results: Between May 2003 and June 2008, 23 patients were started on weekly TV. Median age was 66. Five patients received TV as preoperative treatment for BCs with the following clinical stages: IIB (1); IIIA (1); IIIB (3). The other 18 patients were pathologically staged as: stage I (11); IIA (5); IIIB (2). All cancers were HER2+; 65% of patients also received hormonal treatment for ER/PR+ disease. 3 patients had been previously treated for BC, and received TV as “adjuvant” treatment after a local relapse. Only one of these patients had previously received chemotherapy, while none had received prior T. No pathological complete response was found at surgery after preoperative TV. TV was very well tolerated, with one patient developing febrile neutropenia, 4 patients grade 3–4 uncomplicated neutropenia, and no other grade 3–4 events. During therapy, 5 patients had an asymptomatic 10–20% drop in the LVEF (Grade 1). Follow-up MUGA scans at 1 year after TV so far failed to show any significant abnormality. At an average follow-up of 26 months, one patient died for non-BC related causes, and all the other 22 patients are disease-free. Conclusions: TV is safe and very well tolerated, with no significant cardiac toxicity in our patient population. Preliminary follow-up data suggest that TV may be an acceptable alternative (neo-)adjuvant therapy for patients refusing “toxic” chemotherapy. Further studies prospectively testing TV as adjuvant treatment should be considered for patients with stage 1A BC, for which no standard treatment is clearly defined. No significant financial relationships to disclose.
Increased risk of thrombosis with lenalidomide in combination with dexamethasone and erythropoietin
Authors: R. Niesvizky, A. Spencer, M. Wang, D. Weber, C. Chen, M. A. Dimopoulos, Z. Yu, Z. Yu, R. Delap, J. Zeldis, R. D. Knight
Journal: Journal of Clinical Oncology (2006)

7506 Background: Lenalidomide (Len) is a novel, orally administered, immunomodulatory drug (IMiD) that has single-agent activity against multiple myeloma (MM) and additive effects when combined with dexamethasone (Dex). At the interim analysis of MM-009/010, lenalidomide/dexamethasone achieved a significant benefit over dexamethasone, providing a longer median time to progression (TTP), higher response rates, and higher CR rates. Aim: This subgroup analysis of MM-009/010 was performed to evaluate thrombosis in patients receiving Len/Dex vs Dex. Thrombotic events included the following adverse event terms: thrombosis, deep venous thrombosis, thromboembolism, and pulmonary embolism. Methods: Patients (pts) with relapsed or refractory MM were randomized to either receive oral Len (25 mg daily for 3 weeks every 4 weeks) plus Dex (40 mg on Days 1–4, 9–12, 17–20 every 4 weeks for 4 months, then 40 mg on Days 1–4 every cycle thereafter) or placebo plus Dex. Results: Thrombotic events were reported in 39 (11.3%) of 346 pts treated with Len/Dex compared to 13 (3.8%) of 346 pts treated with Dex alone (p &lt; 0.001). Multivariate analysis identified Len/Dex treatment and erythropoietic treatment to be independently correlated with thrombosis (Table). Older age, lower plasma cell percentage in marrow, and better ECOG performance status had a weaker association with thrombosis. Thrombosis occurred more frequently among pts with prior history of thrombosis, although that was not a significant predictor in the multivariate anlaysis. None of 23 pts who used aspirin or salicylate during the first month of treatment developed thrombosis and all events occurred in pts with rising M-paraprotein levels at baseline. Conclusions: The current study findings suggest that the administration of erythropoietic agents should be minimized in MM pts receiving Len/Dex. Prophylactic antithrombotic therapy should also be considered. [Table: see text] [Table: see text]
Multi-institutional registry for prostate cancer radiosurgery: An observational clinical trial.
Authors: Debra Freeman
Journal: Journal of Clinical Oncology (2015)

98 Background: To report on the design, methodology and early outcome results of a multi-institutional registry study of prostate cancer radiosurgery. Methods: The Registry for Prostate Cancer Radiosurgery (RPCR) was established in 2010 to further evaluate the efficacy and toxicity of prostate radiosurgery (SBRT) for the treatment of clinically localized prostate cancer. Men with prostate cancer were asked to voluntarily participate in the Registry. Demographic, baseline medical and treatment-related data were collected and stored electronically in a HIPAA-compliant database, maintained by Advertek, Inc. Enrolled men were asked to complete short, multiple choice questionnaires regarding their bowel, bladder and sexual function. Patient-reported outcome forms were collected at baseline and at regular intervals (every 3-6 months) following treatment. Serial PSA measurements were obtained at each visit and included in the collected data. Results: From July 2010 to July 2013, nearly 2,000 men from 45 participating sites were enrolled in the registry. The majority (86%) received radiosurgery as monotherapy. At 2 years follow-up, biochemical disease free survival was 92%. No Grade 3 late urinary toxicity was reported. One patient developed Grade 3 gastrointestinal toxicity (rectal bleeding). Erectile function was preserved in 80% of men &lt;70 yeats old. Overall compliance with data entry was 64%. Conclusions: Stereotactic radiosurgery is an alternative option to conventional radiotherapy for the treatment of organ-confined prostate cancer. The Registry for Prostate Cancer Radiosurgery represents the collective experience of multiple institutions, including community-based cancer centers, with outcome results in keeping with published, prospective trials of prostate SBRT.
A phase II study of temozolomide (TMZ) and pegylated interferon α-2b (PGI) in the treatment of advanced melanoma
Authors: S. E. Krown, W.-J. Hwu, J. H. Menell, K. S. Panageas, L. A. Lamb, S. Aird, L. J. Williams, P. B. Chapman, P. O. Livingston, J. D. Wolchok
Journal: Journal of Clinical Oncology (2004)

7533 Background: Interferon-α (IFN) has some anti-tumor activity against melanoma, but has been used primarily at high, toxic doses. At low doses, IFN has antiangiogenic activity and has induced regression of life-threatening childhood hemangiomas. PGI is better tolerated and more effective than conventional IFN in treating hepatitis C. We hypothesized that low-dose PGI might act additively or synergistically with the cytotoxic agent, TMZ in the treatment of malignant melanoma. A phase II study of this combination was initiated in chemotherapy-naïve melanoma patients (pts) to determine response rate and toxicity. Methods: Eligible pts had measurable, unresectable stage III or IV melanoma without brain metastases. TMZ 75 mg/m2/day by mouth for 6 weeks was followed by a 2-week break, and PGI 0.5mcg/kg/week was given subcutaneously for 8 weeks. Response was evaluated at the end of each 8-week cycle. Results: 30 pts (16 men, 14 women; median age 55, range 31–85) with stage IV melanoma (6 M1a, 6 M1b, and 18 M1c) were entered. Median KPS was 90% (range 70–90). 24 pts have completed at least 1 treatment cycle. There were 7 major responses (29%), including 1 CR in soft tissue and liver and 6 PRs in lung, other viscera, soft tissue and lymph nodes. 3 pts were stable and 14 progressed. Median survival was 8.5 mos (95% CI 7.17, 17.9). Median followup among the 18 survivors was 3.3 mos (range .56–21.91). Frequent non-hematologic toxicities ≥grade 2 included vomiting (11), rash (11), fatigue (8), nausea (6), infection without neutropenia (5), injection site reaction (5), elevated ALT (4), and drowsiness (3). Grade 3 lymphopenia occurred in 11 pts; 1 pt had grade 3 leukopenia. Conclusions: The combination of TMZ with low-dose PGI is well tolerated and effective in patients with advanced melanoma without brain metastases and merits further study. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough Schering-Plough
Being married is linked to better outcomes from cardiac surgery
Authors: Zosia Kmietowicz
Journal: BMJ (2015)

Being divorced, separated, or widowed increases the chance of dying or developing a new disability after cardiac surgery, a study has found. Targeting interventions aimed at improving recovery may help to reduce adverse outcomes in these groups, the researchers said.1

Previous research has found that married people may be more likely than unmarried people to survive surgery, but little is known about postoperative function. To assess …
Expression of FLT3 and VEGFR1 on myeloid derived suppressor cells (MDSC) in renal cell carcinoma (RCC) patients (Pts)
Authors: S. George, P. Rayman, S. Biswas, T. Smith-Williams, J. S. Ko, L. Wood, P. Elson, B. I. Rini, R. M. Bukowski, J. H. Finke
Journal: Journal of Clinical Oncology (2008)

5108 Background: MDSC are immature myeloid cells (CD15+ CD14- CD33+ HLADR- and CD11b+) that are over expressed and are immunosuppressive in cancer pts including RCC. The goal of this study was to determine whether MDSC express VEGFR1 and FLT3 and can be modulated by sunitinib or by surgical resection of tumor. Methods: Peripheral blood mononuclear cells (PBMC) were analyzed by flow cytometry for the presence of MDSC and their expression of VEGFR1 and FLT3 from the following populations; age matched normals (AMN), metastatic RCC (mRCC) pts (samples at baseline and after 4 cycles of sunitinib treatment) and localized RCC (LRCC) pts (before and 6 weeks post surgery). RECIST-defined response data in mRCC pts was collected at the PBMC sample time points. Statistical methods included Wilcoxon rank sum and signed rank tests. Results: PBMC samples of 7 AMN, 6 LRCC pts and 12 mRCC pts were analyzed. The percentage of MDSC (CD14- CD15+ and CD33+HLADR-) were elevated in both LRCC (p=.008) and MRCC pts (p<.04) compared to AMN. When analyzing samples from both LRCC and MRCC, VEGFR1 was expressed on 28% of MDSC while 17% of MDSC expressed FLT3. Moreover, the percentage of both VEGFR1+ (p=<.003) and FLT3+ (p=<.02) MDSC were increased in RCC pts compared to AMN. While sunitinib-treated pts had a decrease in the total MDSC (CD15+ p=.09; CD33+ p=.04) compared to baseline, there was no significant difference in the levels of the VEGFR1 and FLT3 positive MDSC from the baseline after 4 cycles of sunitinib. mRCC pts with tumor volume increase following sunitinib therapy tended to have increase in the overall FLT3 population (p=.07) compared to others. Surgical removal of tumor showed a trend in decreasing MDSC (CD33+ p=.06), although the VEGFR1+ and FLT3 + MDSC did not change significantly from baseline. Conclusions: VEGFR1 and FLT3 receptors are expressed on a subset of MDSC, which are over expressed in RCC pts. This subset of MDSC with the above receptors appears to be resistant to reduction after sunitinib treatment compared to the MDSC lacking these receptors. The role of VEGFR1, FLT3 and other receptors in promoting MDSC accumulation remains to be defined. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Antigenics, Bayer, Genentech™ BioOncology, Novartis, Onyx, Pfizer Oncology, Wyeth Bayer, Genentech™ BioOncology, Novartis, Onyx, Pfizer Oncology, Wyeth Bayer, Genentech™ BioOncology, Pfizer Oncology, Wyeth
A phase II trial of erlotinib (OSI-774) in patients (pts) with recurrent malignant gliomas (MG) not on EIAEDs
Authors: J. J. Raizer, L. E. Abrey, P. Wen, T. Cloughesy, I. A. Robins, H. A. Fine, F. Lieberman, V. K. Puduvalli, K. L. Fink, M. Prados
Journal: Journal of Clinical Oncology (2004)

1502 Purpose: To evaluate the efficacy of OSI-774, a small molecule tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), in patients with recurrent malignant gliomas not on enzyme induce anti-convulsant drugs (EIAEDs). Methods: Pts with recurrent MG were treated with OSI-774 at a dose of 150 mg/day continuously. Patients could not have had more than 2 prior chemotherapies. Patients were evaluated for response with MRI every 56 days. PK studies and AGP levels were done in most patients. Results: 67 pts enrolled onto this arm of the study but only the 45 pts with recurrent MG are reported here. Histology: 30 (20M/10F) pts had glioblastoma multiformes (GBMs) and 15 (7M/8F) pts had anaplastic gliomas (AGs). Median age and KPS was 58 years and 80 for GBMs and 43 years and 90 for AGs. The median PFS for GBM was 12 wks (95% CI; 7.6 to 13 weeks) with no GBM pts progression free at 24 weeks; best response was SD in 4 pts. For AGs median PFS was 8.6 wks (CI; 3.7 to 45 wks) with 4 patients still on study; best response was 1 PR (unconfirmed) and 2 SD. Cycle 1 toxicities: Gr 3-Rash and hypokalemia all others were Gr 1 and 2, primarily rash, diarrhea, fatigue, and bilirubin elevation. PK studies on 20 pts, found an AUC0–24 for OSI-774 was 13.1 ugxh/ml and for OSI-420 875 ngxh/ml; the Cpmax (ng/ml) was 895 and 64 for OSI-774 and OSI-420. Conclusion: We completed a phase II trial of OSI-774 in patients with MGs not on EIAEDs. While a few patients had SD and 1 had a PR the median PFS and the 24 week PFS suggest that for GBMs and AGs that OSI-774 has limited activity as a single agent. Toxicities were primarily Gr 1 and 2 and tolerable. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech
Modulation of pharmacodynamic (PD) biomarkers in dermal biopsies from patients treated on a phase I study of bevacizumab (Bev) in combination with everolimus (Ev) and erlotinib (Erl) for advanced solid tumors.
Authors: Jingquan Jia, Haiyan Li, Andrew Dellinger, Herbert Pang, Karen Bullock Russell, Herbert Hurwitz, Andrew B. Nixon
Journal: Journal of Clinical Oncology (2012)

e13589 Background: Tumor growth and angiogenesis are regulated by multiple cellular pathways, including the VEGF, mTOR, and EGFR pathways. We have previously reported our clinical experience combining Bev, Ev and Erl therapies. Taking advantage of the similarities between tumor growth and wound healing, we conducted a PD analysis of these agents using novel dermal wound angiogenesis assays. Methods: Patients with advanced solid tumors received either 1) Bev-Ev doublet therapy; 2) Bev-Ev-Erl triplet therapy; 3) Ev monotherapy for 14 days followed by addition of Bev-Erl; 4) Erl monotherapy for 14 days followed by addition of Bev-Ev. Full-thickness dermal granulation biopsies were harvested; the phospho (p) and total (t) levels of VEGFR2, EGFR, and S6RP were measured at baseline, end of the monotherapy lead-in period (day 14), and 35 days post doublet or triplet therapy. A dermal wound angiogenesis assay, which quantifies peripheral wound vascularization was also incorporated in the study. Results: 38 pts were evaluable for biomarker analysis. Wilcoxon signed rank tests indicated that both VEGFR2 and S6RP were significantly down-regulated after Bev-Ev-Erl triplet therapy: tVEGFR2 (q=5.1E-05), pVEGFR2 (q=0.01), tS6RP (q=0.007), pS6RP (q=9.7E-04). Levels of tVEGFR2 (q=5.5E-04) and pS6RP (q=6.9E-04) were also found to be significantly down-regulated after Bev-Ev doublet therapy. Ev monotherapy for 14 days led to significant tVEGFR2 down-regulation (q=0.035). No significant changes in EGFR levels were observed in any cohort. Additionally, Bev-Ev-Erl triplet therapy led to a slight decrease in dermal wound vascularization (p=0.098), which positively correlated with changes in tVEGFR2 levels (q=0.008). Conclusions: This is the first investigation evaluating the PD effects of VEGF, mTOR, and EGFR inhibition in a clinical wound-healing model. Our results indicate that targeting of all three pathways is associated with overall down-regulation of both VEGF and mTOR pathways. These data suggest that this dermal wound model can be used to quantify PD markers in evaluating multiple classes of targeted therapies.
Current status of phase III anti-EGF-receptor antibody (OSAG-101) for newly diagnosed glioblastoma.
Authors: M. Westphal, C. Senft, C. Braun, T. Pietsch, M. Warmuth, F. Bach, O. Heese
Journal: Journal of Clinical Oncology (2010)

2056 Background: EGF-R is the most consistently expressed cell surface marker for glioblastoma. Therapies are directed against the intercellular signalling pathway or the cell surface binding of the cognate ligands. Because of the selectivity of this molecule for gliomas and promising preclinical and early clinical findings, to evaluate the therapeutic effect of a monoclonal antibody (nimotuzumab) which has a lower affinity than cetuximab, thus binding more specifically to highly overexpressing cells is warranted in a phase III design. Methods: Nimotuzumab (OSAG-101) is tested in an open label, randomized, multicenter phase III trial in patients with newly diagnosed glioblastoma. OSAG-101 is administered by i.v. infusion (weekly infusion of 400 mg) on top of the current standard radiochemotherapy with temozolamide followed by biweekly infusions of 400 mg thereafter until progression. Patients with histologically confirmed glioblastoma were included without specification of resection status. Patients under the age of 18 and over 70 years were excluded. Primary endpoint was time to progression as determined by centralized neuro-imaging review using a standardized evaluation protocol. Overall survival serves as a secondary endpoint with quality of life and safety as additional parameters. Results: Between August 2008 and December 2009, 130 patients were enrolled in 10 sites with 150 subjects. All except one patient were GBM on central histopathological review. 60 patients had a gross total resection with no residual contrast enhancement and 70 patients had partial resections with residual contrast enhancement, including patients with biopsy only. The observed adverse reaction pattern was the same in both study arms and both strata and reflecting the event pattern of the disease and its standard treatment. No rash, conjunctivitis or mucositis were reported. Conclusions: The intravenous administration of OSAG-101 for newly diagnosed glioblastoma is safe and free of additional toxicity to the standard radiochemotherapy regimen. With 75 patients just having reached their primary endpoint, an interim analysis will be available by march 2010. Accrual is expected to be complete by April 2010. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Oncoscience
PSA nadir and 24 month biopsy interim analysis of AdV-tk/Valacyclovir gene therapy in combination with radiotherapy vs radiotherapy alone for prostate cancer
Authors: L. K. Aguilar, B. S. Teh, G. Ayala, M. T. Vlachaki, T. Wheeler, D. Kadmon, T. Thompson, B. Miles, E. Aguilar-Cordova, E. B. Butler
Journal: Journal of Clinical Oncology (2004)

4571 Background: A Phase II clinical trial for newly diagnosed, non-metastatic prostate cancer is ongoing in which adenoviral-HSV thymidine kinase (AdV-tk) + prodrug (valacyclovir) is added to standard-of-care radiation and hormonal therapy. This study is based on animal models demonstrating increased local and systemic anti-tumor efficacy from AdV-tk combined with radiation. Methods: Subjects receive transrectal ultrasound guided intratumoral injection of 5x1011 particles of AdV-tk followed by oral administration of valacyclovir for 14 days per cycle. Intensity modulated radiation therapy (IMRT) is used for all patients with a mean dose of 76Gy. The study is divided into: Arm A: low risk patients (T1-T2a, Gleason<7, PSA<10) receive two cycles of AdV-tk on days 0 and 14 with radiotherapy starting on day 2. Arm B: high risk patients (T2b-T3, Gleason>6, PSA>10) receive three cycles of AdV-tk on days 0, 56 and 70, hormone therapy (LHRH-agonist and flutamide) started on day 0 and radiotherapy on day 58. Arm C: stage D1 (positive lymph node) receive the same regimen as Arm B with an additional 45Gy to pelvic lymphatics. Results: To date, 70 patients have been treated (33 in Arm A, 32 in Arm B, 5 in Arm C) with an overall median follow up time of 39 months and no significant toxicity. Of the 30 subjects in Arm A which have PSA data more than 18 months after completion of radiotherapy, 25 (83%) have reached a PSA nadir of ≤0.5 which is significantly more than expected based on a control group (67%) which received radiotherapy alone (p<0.025). Of 30 available sextant biopsies from Arm A and B at 24 months (15 from each), 28 were negative (93%). This frequency is significantly higher than previous reports with radiotherapy alone (51% from Crook et al, 2000 (p=0.000001) and 70% from Pollack et al, 2002 (p<0.002). Conclusions: The combination of AdV-tk gene therapy and radiation has been well tolerated, is feasible to deliver as an outpatient procedure and early results of surrogate markers for treatment efficacy are positive. The efficacy of this novel approach will need to be validated by a prospective randomized study. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Advantagene Advantagene Advantagene