A Multicenter, Phase II, Randomized, Noncomparative Clinical Trial of Radiation and Temozolomide with or without Vandetanib in Newly Diagnosed Glioblastoma Patients.

PURPOSE: Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, noncomparative, phase II study of radiation (RT) and temozolomide with or without vandetanib in patients with newly diagnosed glioblastoma (GBM). EXPERIMENTAL DESIGN: We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and temozolomide with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age ≥ 18 years, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis. RESULTS: The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 patients (36 in the RT/temozolomide arm and 70 in the vandetanib/RT/temozolomide arm). Median OS was 15.9 months [95% confidence interval (CI), 11.0-22.5 months] in the RT/temozolomide arm and 16.6 months (95% CI, 14.9-20.1 months) in the vandetanib/RT/temozolomide (log-rank P = 0.75). CONCLUSIONS: The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or gliosarcoma was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong OS compared with the parallel control arm, leading to early termination of the study.

Phase II study of monthly pasireotide LAR (SOM230C) for recurrent or progressive meningioma.

OBJECTIVE: A subset of meningiomas recur after surgery and radiation therapy, but no medical therapy for recurrent meningioma has proven effective. METHODS: Pasireotide LAR is a long-acting somatostatin analog that may inhibit meningioma growth. This was a phase II trial in patients with histologically confirmed recurrent or progressive meningioma designed to evaluate whether pasireotide LAR prolongs progression-free survival at 6 months (PFS6). Patients were stratified by histology (atypical [World Health Organization grade 2] and malignant [grade 3] meningiomas in cohort A and benign [grade 3] in cohort B). RESULTS: Eighteen patients were accrued in cohort A and 16 in cohort B. Cohort A had median age 59 years, median Karnofsky performance status 80, 17 (94%) had previous radiation therapy, and 11 (61%) showed high octreotide uptake. Cohort B had median age 52 years, median Karnofsky performance status 90, 11 (69%) had previous radiation therapy, and 12 (75%) showed high octreotide uptake. There were no radiographic responses to pasireotide LAR therapy in either cohort. Twelve patients (67%) in cohort A and 13 (81%) in cohort B achieved stable disease. In cohort A, PFS6 was 17% and median PFS 15 weeks (95% confidence interval: 8-20). In cohort B, PFS6 was 50% and median PFS 26 weeks (12-43). Treatment was well tolerated. Octreotide uptake and insulin-like growth factor-1 levels did not predict outcome. Expression of somatostatin receptor 3 predicted favorable PFS and overall survival. CONCLUSIONS: Pasireotide LAR has limited activity in recurrent meningiomas. The finding that somatostatin receptor 3 is associated with favorable outcomes warrants further investigation. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with recurrent or progressive meningioma, pasireotide LAR does not significantly increase the proportion of patients with PFS at 6 months.

Phase I study of vandetanib with radiotherapy and temozolomide for newly diagnosed glioblastoma.

PURPOSE: Increasing evidence has suggested that angiogenesis inhibition might potentiate the effects of radiotherapy and chemotherapy in patients with glioblastoma (GBM). In addition, epidermal growth factor receptor inhibition might be of therapeutic benefit, because the epidermal growth factor receptor is upregulated in GBM and contributes to radiation resistance. We conducted a Phase I study of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, in patients with newly diagnosed GBM combined with RT and temozolomide (TMZ). METHODS AND MATERIALS: A total of 13 GBM patients were treated with vandetanib, radiotherapy, and concurrent and adjuvant TMZ, using a standard "3 + 3" dose escalation. The maximal tolerated dose was defined as the dose with <1 of 6 dose-limiting toxicities during the first 12 weeks of therapy. The eligible patients were adults with newly diagnosed GBM, Karnofsky performance status of >or=60, normal organ function, who were not taking enzyme-inducing antiepileptic drugs. RESULTS: Of the 13 patients, 6 were treated with vandetanib at a dose of 200mg daily. Of the 6 patients, 3 developed dose-limiting toxicities within the first 12 weeks, including gastrointestinal hemorrhage and thrombocytopenia in 1 patient, neutropenia in 1 patient, and diverticulitis with gastrointestinal perforation in 1 patient. The other 7 patients were treated with 100 mg daily, with no dose-limiting toxicities observed, establishing this dose as the maximal tolerated dose combined with TMZ and RT. CONCLUSION: Vandetanib can be safely combined with RT and TMZ in GBM patients. A Phase II study in which patients are randomized to vandetanib 100 mg daily with RT and TMZ or RT and TMZ alone is underway.

Personal touch: personal health records for consumers of healthcare.

Personal health records (PHRs) consist of medical records that the consumer collects from each of their healthcare providers, plus any health information that the consumer adds. Sharing information from the PHR with providers enables the consumer and provider to work together. Use of data in the PHR can help reduce or eliminate duplicate procedures or processes. This helps save time and healthcare dollars. It can help the consumer receive better, more coordinated healthcare. In addition, PHRs will eventually have the impact of empowering consumers as never before to make informed healthcare choices and have a positive impact on the overall cost of healthcare. This article is part of a series of unpublished essays titled A Community View on How Personal Health Records Can Improve Patient Care and Outcomes in Many Healthcare Settings, a collaborative project of Northern Illinois Physicians For Connectivity and the Coalition for Quality and Patient Safety of Chicagoland. For further information on how you can obtain copies of the complete work, contact the principle Dr. Stasia Kahn at Stash5@sbcglobal.net.

Clinical trial of standing-orders strategies to increase the inpatient influenza vaccination rate.

We compared strategies to increase the rate of influenza vaccination. A written standing-orders policy that enabled nurses to vaccinate patients was compared with augmentation of the standing-orders policy with either electronic opt-out orders for physicians or electronic reminders to nurses. Use of opt-out orders yielded the highest vaccination rate (12% of patients), followed by use of nursing reminders (6%); use of the standing-orders policy alone was ineffective.

An exploratory survival analysis of anti-angiogenic therapy for recurrent malignant glioma.

Recent clinical trial results suggest that anti-angiogenic therapy may be effective against recurrent malignant glioma. Though these treatments prolong progression-free survival, the extent to which they prolong overall survival is unknown. We pooled data from 34 patients treated at a single institution on phase II clinical trials of bevacizumab and cediranib, and we compared these data to 18 patients treated on clinical trials of cytotoxic chemotherapies. In univariate and multivariate analyses, treatment group was a significant predictor of progression-free but not overall survival. Median progression-free survival was 8 vs. 22 weeks in patients treated with cytotoxic as compared to anti-angiogenic therapy (P = 0.01). Median overall survival was nearly identical in the two groups (39 vs. 37 weeks). The results of this exploratory analysis suggest that anti-angiogenic therapy may fail to prolong overall survival in patients with recurrent malignant glioma. If this conclusion proves correct, progression-free survival may be an inappropriate endpoint for phase II trials of anti-angiogenic therapies.

Use of clinical decision support to increase influenza vaccination: multi-year evolution of the system.

Despite recognition that clinical decision support (CDS) can improve patient care, there has been poor penetration of this technology into healthcare settings. We used CDS to increase inpatient influenza vaccination during implementation of an electronic medical record, in which pharmacy and nursing transactions increasingly became electronic. Over three influenza seasons we evaluated standing orders, provider reminders, and pre-selected physician orders. A pre-intervention cross-sectional survey showed that most patients (95%) met criteria for vaccination. During our intervention, physicians were increasingly likely to accept pre-selected vaccination orders, Year 1 (47%), Year 2 (77%), Year 3 (83%); however vaccine administration by nurses was suboptimal. As electronic medical record functionality improved, patient receipt of vaccine increased dramatically, Year 1 [0/36; 0%], Year 2 [8/66; 12%], Year 3 [286/805; 36%]. Successful use of clinical decision support to increase inpatient influenza vaccination only occurred after initiation of CPOE for all medications and integration of an electronic medication administration record. Also, since most patients met criteria for influenza vaccination, complicated logic to identify high-risk patients was unnecessary.

Deep brain stimulation of the nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug seeking in rats.

Increasing evidence suggests that deep brain stimulation (DBS), which is currently being used as a therapy for neurological diseases, may be effective in the treatment of psychiatric disorders as well. Here, we examined the influence of DBS of the nucleus accumbens shell on cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.25 mg, i.v.) 2 h daily for 21 d and then cocaine-seeking behavior was extinguished by replacing cocaine with saline. During the reinstatement phase, DBS was administered bilaterally to the nucleus accumbens shell through bipolar stainless steel electrodes. Biphasic symmetrical pulses were delivered at a frequency of 160 Hz and a current intensity of 150 muA. DBS began immediately after a priming injection of cocaine (0, 5, 10, or 20 mg/kg, i.p.) and continued throughout each 2 h reinstatement session. Results indicated that only the higher doses of cocaine (10 and 20 mg/kg) produced robust and reliable reinstatement of cocaine seeking. DBS of the nucleus accumbens shell significantly attenuated the reinstatement of drug seeking precipitated by these higher cocaine doses. Additional experiments indicated that this DBS effect was both anatomically and reinforcer specific. Thus, DBS of the dorsal striatum had no influence on cocaine reinstatement and DBS of the accumbens shell did not affect the reinstatement of food seeking. Together, these results suggest that DBS of the nucleus accumbens shell may be a potential therapeutic option in the treatment of severe cocaine addiction.

House staff attitudes about influenza vaccination after participation in a clinical trial to improve vaccination of hospital patients.

We surveyed house staff who had participated in a trial that compared influenza vaccination strategies for inpatients. House staff who were exposed to computer-generated vaccination orders were more likely to report that they recommended vaccination to their inpatients and outpatients, compared with house staff who were not exposed to a vaccination intervention. Also, house staff did not recognize pregnant women as a high-priority population for influenza vaccination.

Evolution of clinical decision support to increase influenza vaccination.

Over three influenza seasons spanning four years we evaluated the effect of standing orders, reminders, and iterations of Clinical Decision Support (CDS) to increase influenza (flu) vaccination among inpatients. Using CDS, coverage increased over each season: (0%, 12%, 35%). However, success was realized only after integration of the electronic medication administration record (E-MAR). Standing orders and reminders were ineffective.