Deborah Allen

Cediranib for Metastatic Alveolar Soft Part Sarcoma

PURPOSE Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs). PATIENTS AND METHODS We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging. RESULTS Of 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis. CONCLUSION In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib.

Phase 2 trial of BCNU plus irinotecan in adults with malignant glioma

In preclinical studies, BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, plus CPT-11 (irinotecan) exhibits schedule-dependent, synergistic activity against malignant glioma (MG). We previously established the maximum tolerated dose of CPT-11 when administered for 4 consecutive weeks in combination with BCNU administered on the first day of each 6-week cycle. We now report a phase 2 trial of BCNU plus CPT-11 for patients with MG. In the current study, BCNU (100 mg/m2) was administered on day 1 of each 6-week cycle. CPT-11 was administered on days 1, 8, 15, and 22 at 225 mg/m2 for patients receiving CYP3A1- or CYP3A4-inducing anticonvulsants and at 125 mg/m2 for those not on these medications. Newly diagnosed patients received up to 3 cycles before radiotherapy, while recurrent patients received up to 8 cycles. The primary end point of this study was radiographic response, while time to progression and overall survival were also assessed. Seventy-six patients were treated, including 37 with newly diagnosed tumors and 39 with recurrent disease. Fifty-six had glioblastoma multiforme, 18 had anaplastic astrocytoma, and 2 had anaplastic oligodendroglioma. Toxicities (grade > or =3) included infections (13%), thromboses (12%), diarrhea (10%), and neutropenia (7%). Interstitial pneumonitis developed in 4 patients. Five newly diagnosed patients (14%; 95% CI, 5%-29%) achieved a radiographic response (1 complete response and 4 partial responses). Five patients with recurrent MG also achieved a response (1 complete response and 4 partial responses; 13%; 95% CI, 4%-27%). More than 40% of both newly diagnosed and recurrent patients achieved stable disease. Median time to progression was 11.3 weeks for recurrent glioblastoma multiforme patients and 16.9 weeks for recurrent anaplastic astrocytoma/ anaplastic oligodendroglioma patients. We conclude that the activity of BCNU plus CPT-11 for patients with MG appears comparable to that of CPT-11 alone and may be more toxic.

Gefitinib (Iressa¿, ZD1839) and Tyrosine Kinase Inhibitors: The Wave of the Future in Cancer Therapy

Targeted therapies are one of the latest innovative trends in cancer therapy. The epidermal growth factor receptor (EGFR) is a target found in high concentrations in several solid tumors including lung, breast, colorectal, and brain. Tyrosine kinase inhibitors, such as gefitinib (IressaTM, ZD1839), block the EGFR. As a result, there is inhibition of cellular proliferation, promotion of apoptosis, and inhibition of anti-angiogenesis. Gefitinib has demonstrated significant efficacy in non-small-cell lung cancer (NSCLC), leading to FDA approval for treatment of this refractory disease. Phase 2 trials with gefitinib for platinum refractory NSCLC reported disease response and symptom improvement. Early results of phase 2 studies of gefitinib, combined with standard chemotherapy in colorectal cancer, showed a 75% response rate compared with 55% with standard therapy alone. Gefitinib, combined with flutamide, produced an additive growth inhibition in prostate cancer. A phase 2 trial of gefitinib in first-relapse glioblastoma multiforme demonstrated median overall survival from treatment start of 39.4 weeks compared with 40 weeks with standard chemotherapy. Gefitinib is an oral agent with a mild toxicity profile, and thus, may be an optimal addition to chemotherapeutic regimens for some solid tumors. Gefitinib is potentially a vital and useful weapon in the arsenal of cancer therapies.

Putting Evidence Into Practice: Evidence-Based Interventions for Cancer and Cancer Treatment-Related Cognitive Impairment

Cognitive impairment is a clinically complex symptom commonly experienced by cancer survivors. Although research in this area has grown, many questions remain regarding underlying mechanisms, trajectory, and specific interventions nurses can offer patients to prevent, treat, and manage cognitive impairment effectively. As part of the Oncology Nursing Society (ONS) Putting Evidence Into Practice (PEP) initiative, a comprehensive examination of the current literature was conducted to identify effective interventions for cognitive impairment in cancer survivors. The studies were categorized into nonpharmacologic interventions, including complementary and alternative therapies and cognitive training, and pharmacologic interventions, including psychostimulants and erythropoietin-stimulating agents. Using the ONS PEP Weight of Evidence Classification Schema, the levels of evidence for these interventions were consistent with the categories of effectiveness not established or not recommended for practice. Additional research is needed to identify effective preventive and treatment strategies for cognitive impairment in cancer survivors.

Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma

Irinotecan is a topoisomerase I inhibitor previously shown to be active in the treatment of malignant glioma. We now report the results of a phase 1 trial of irinotecan plus BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, for patients with recurrent or progressive MG. Irinotecan dose escalation occurred independently within 2 strata: patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and patients not receiving EIAEDs. BCNU was administered at a dose of 100 mg/m2 over 1 h every 6 weeks on the same day as the first irinotecan dose was administered. Irinotecan was administered intravenously over 90 min once weekly. Treatment cycles consisted of 4 weekly administrations of irinotecan followed by a 2-week rest with dose escalation in cohorts of 3 to 6 patients. Seventy-three patients were treated, including 49 patients who were on EIAEDs and 24 who were not on EIAEDs. The maximum tolerated dose for patients not on EIAEDs was 125 mg/m2. The maximum tolerated dose for patients on EIAEDs was 225 mg/m2. Dose-limiting toxicity was evenly distributed among the following organ systems: pulmonary, gastrointestinal, cardiovascular, neurologic, infectious, and hematologic, without a clear predominance of toxicity involving any one organ system. There was no evidence of increasing incidence of toxicity involving one organ system as irinotecan dose was escalated. On the basis of these results, we conclude that the recommended doses of irinotecan for a phase 2 clinical trial when given in combination with BCNU (100 mg/m2) are 225 mg/m2 for patients on EIAEDs and 125 mg/m2 for patients not on EIAEDs.

Phase I trial of vandetanib and bevacizumab evaluating the VEGF and EGF signal transduction pathways in adults with solid tumours and lymphomas

PURPOSE Inhibition of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) pathways may result in synergistic antitumour activity. We designed a phase I study to evaluate the combination of vandetanib, an investigational agent with activity against EGF receptor and VEGF receptor 2, and bevacizumab, a monoclonal antibody against VEGF. EXPERIMENTAL DESIGN Patients with advanced solid tumours and lymphomas were enrolled. Objectives were to determine the safety and maximum tolerated dose of the combination, characterise pharmacokinetics, measure angiogenic marker changes in blood, and assess tumour blood flow using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Vandetanib was given orally once daily and bevacizumab intravenously once in every 3 weeks in 21-day cycles utilising a standard dose-escalation design. RESULTS Fifteen patients were enrolled, and a total of 94 cycles of therapy were administered. No protocol-defined dose-limiting toxicities were observed; due to toxicities associated with chronic dosing, hypertension, proteinuria, diarrhoea and anorexia, dose escalation was stopped at the second dose level. We observed one partial response and one minor response; 9 patients experienced stable disease. There were significant changes in plasma VEGF and placental-derived growth factor levels, and decreases in K(trans) and k(ep) were observed by DCE-MRI. CONCLUSION In this trial, we safely combined two targeted agents that cause dual blockade of the VEGF pathway, demonstrated preliminary evidence of clinical activity, and conducted correlative studies demonstrating anti-angiogenic effect. The recommended phase II dose was established as vandetanib 200 mg daily and bevacizumab 7.5 mg/kg every 3 weeks.

Enabling nurses to lead change: The orientation experiences of nurses to boards

OBJECTIVES Nurses need to be full partners in shaping health care and health care policy. One way to do this is to be present and active on boards at all levels. The purpose of this study is to examine the orientation experiences of nurses to boards and their preparation to influence health care and health care policy. METHODS A Web-based survey about the efficacy of board orientation was sent to members of three local boards made up exclusively of nurses. RESULTS Liabilities and fiduciary duties were least likely to be addressed in board orientation for nurses. Board members requested more training in finance and a more formal/structured orientation process. CONCLUSIONS Standardizing orientation elements for nurses serving on boards would best prepare them to serve on interprofessional hospital boards and work in the health policy arena. The orientation experience on local- and state-level nursing boards is fundamental to nurses beginning board service.

Early palliative care on an inpatient oncology unit: Impact of a novel co-rounding partnership on patient and health system outcomes.

3 Background: Early palliative care (PC) improves outcomes for outpatients with advanced cancer, but its impact on an inpatient oncology unit is unknown. We implemented a novel inpatient medical oncology (ONC) and PC co-rounding partnership on September 1, 2011 at Duke University Hospital. Here we report its impact on patient and health system outcomes during its first year of implementation. METHODS We extracted patient data including demographics, cancer diagnosis, disease status, length of stay (LOS), ICU transfer rate, discharge disposition, time to ER return, time to readmission, and 7- and 30-day ER return and readmission rates (RR). Pre- and post-intervention cohorts were defined as all patients admitted or transferred to the solid tumor inpatient service from September 1, 2009-June 30, 2010 and September 1, 2011-June 30, 2012, respectively. Nursing and physician surveys assessed satisfaction. We used descriptive statistics, Students t-test, and Fishers exact test for analyses. RESULTS The pre- and post-intervention analysis cohorts included 731 and 783 patients respectively, representing 2,353 encounters. Cohorts were similar in baseline characteristics, including mean age (61 vs. 62; p=0.07), gender (male: 51% vs. 48%; p=0.22), race (white: 68% vs. 71%; p=0.39), insurance coverage (Medicare: 49% vs. 51%; p=0.96), and disease status (recurrent/metastatic: 73% vs. 74%; p=0.6). Post-intervention patients had a statistically significant decrease in mean LOS (p=0.02) from 4.51 days (95% CI 4.3-4.73) to 4.17 days (95% CI 3.97-4.37), and statistically significant improvements in 7- and 30-day readmission rates, representing a 15% (p=0.03) and 23% (p=0.05) improvement, respectively. We observed a trend for increasing hospice referral (p=0.09) and a 15% decrease in ICU transfers. Physicians and nurses universally favored the model. CONCLUSIONS A fully-integrated, inpatient co-rounding partnership between PC and ONC resulted in statistically significant improvements in key health system-related outcomes and indicators of quality cancer care.

Establishing an Evidence-Based Inpatient Medical Oncology Fluid Balance Measurement Policy

Fluid balance measurement (FBM) is a routine intervention in oncology, but accuracy and compliance issues have been documented. This article describes how a medical oncology nursing clinical practice committee used the Iowa Model for Evidence-Based Practice to establish a policy for FBM. Nursing and medical education was performed with emphasis on oncology-specific defaults in a computerized provider order entry system reflecting the new FBM policy. At two months of implementation, the policy effectively demonstrated improved staff compliance and satisfaction, as well as appropriate orders for patients requiring stricter FBM.

Improvements in Patient and Health System Outcomes Using an Integrated Oncology and Palliative Medicine Approach on a Solid Tumor Inpatient Service

PURPOSE Early palliative care (PC) improves outcomes for outpatients with advanced cancer. Its effect on hospitalized patients with cancer is unknown. Herein, we report on the influence of a novel, fully integrated inpatient medical oncology and PC partnership at a tertiary medical center during its first year of implementation. METHODS We conducted a retrospective, longitudinal, pre- and postintervention cohort study at Duke University Hospital. Pre- and postintervention cohorts were defined as all patients admitted to the solid tumor inpatient service from September 1, 2009, to June 30, 2010, and September 1, 2011 to June 30, 2012, respectively. We extracted patient data, including demographics, cancer diagnosis, disease status, length of stay, intensive care unit transfer rate, discharge disposition, time to emergency department return, time to readmission, and 7- and 30-day emergency department return and readmission rates. Nursing and physician surveys assessed satisfaction. Descriptive statistics, and Kruskal-Wallis and Χ2 tests were used to describe and compare cohorts. A generalized estimating equation accounted for repeated measures. RESULTS Pre- and postintervention analysis cohorts included 731 and 783 patients, respectively, representing a total of 1,514 patients and 2,353 encounters. Cohorts were similar in baseline characteristics. Statistically significant lower odds in 7-day readmission rates were observed in the postintervention cohort (adjusted odds ratio, 0.76; 95% CI, 0.58 to 1.00; P = .0482). Patients in the postintervention group had a decrease in mean length of stay (-0.30 days; 95% CI, -0.62 to 0.02); P = .0651). We observed a trend for increasing hospice referrals ( P = .0837) and a 15% decrease in intensive care unit transfers ( P = .61). Physicians and nurses universally favored the model. CONCLUSION A fully integrated inpatient partnership between PC and medical oncology is associated with significant and clinically meaningful improvements in key health system-related outcomes and indicators of quality cancer care.