Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II ...trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined.
Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously IV once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups.
The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio HR, 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806).
Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.
Azacitidine (AZA) is effective treatment for myelodysplastic syndromes (MDS) at a dosing schedule of 75 mg/m(2)/d subcutaneously for 7 days every 4 weeks. The initial phase of this ongoing ...multicenter, community-based, open-label study evaluated three alternative AZA dosing schedules without weekend dosing.
MDS patients were randomly assigned to one of three regimens every 4 weeks for six cycles: AZA 5-2-2 (75 mg/m(2)/d subcutaneously for 5 days, followed by 2 days no treatment, then 75 mg/m(2)/d for 2 days); AZA 5-2-5 (50 mg/m(2)/d subcutaneously for 5 days, followed by 2 days no treatment, then 50 mg/m(2)/d for 5 days); or AZA 5 (75 mg/m(2)/d subcutaneously for 5 days).
Of patients randomly assigned to AZA 5-2-2 (n = 50), AZA 5-2-5 (n = 51), or AZA 5 (n = 50), most were French-American-British (FAB) lower risk (refractory anemia RA/RA with ringed sideroblasts/chronic myelomonocytic leukemia with < 5% bone marrow blasts, 63%) or RA with excess blasts (30%), and 79 (52%) completed > or = six treatment cycles. Hematologic improvement (HI) was achieved by 44% (22 of 50), 45% (23 of 51), and 56% (28 of 50) of AZA 5-2-2, AZA 5-2-5, and AZA 5 arms, respectively. Proportions of RBC transfusion-dependent patients who achieved transfusion independence were 50% (12 of 24), 55% (12 of 22), and 64% (16 of 25), and of FAB lower-risk transfusion-dependent patients were 53% (nine of 17), 50% (six of 12), and 61% (11 of 18), respectively. In the AZA 5-2-2, AZA 5-2-5, and AZA 5 groups, 84%, 77%, and 58%, respectively, experienced > or = 1 grade 3 to 4 adverse events.
All three alternative dosing regimens produced HI, RBC transfusion independence, and safety responses consistent with the currently approved AZA regimen. These results support AZA benefits in transfusion-dependent lower-risk MDS patients.
Summary
Purpose
Gemcitabine (G) is standard therapy for pancreatic cancer. Enzastaurin (E) inhibits PKCβ and PI3K/AKT signaling pathways with a dose-dependent effect on growth of pancreatic carcinoma ...xenografts. Data suggest that the GE combination may improve clinical outcomes.
Methods
Primary objective was overall survival (OS); secondary objectives assessed progression-free survival (PFS), response rate (RR), quality of life (QOL), toxicity, and relationships between biomarker expression and clinical outcomes. Patients were randomly assigned (2:1) to GE or G treatment; GE arm: E 500 mg PO daily; loading-dose (1200 mg; Day 1 Cycle 1 only) and G 1000 mg/m
2
IV Days 1, 8, and 15 in 28-day cycles; G arm: G as in GE. Biomarker expression was assessed by immunohistochemistry.
Results
Randomization totaled 130 patients (GE = 86, G = 44); 121 patients were treated (GE = 82, G = 39). GE/G median OS was 5.6/5.1 months; median PFS was 3.4/3.0 months. GE responses: 1 complete response (CR, 1.2%), 6 partial response (PR, 7.4%), and 33 stable disease (SD, 40.7%); disease control rate (DCR=CR+PR+SD, 49.4%). G responses: 2 PR (5.3%) and 16 SD (42.1%); DCR (47.4%). No QOL differences were noted between arms. GE/G Grade 3–4 toxicities included: neutropenia (18.3%/28.2%); thrombocytopenia (14.6%/25.6%); and fatigue (11.0%/7.7%). No statistically significant relationships between biomarker expression and outcomes were observed. However, patients with low expression of cytoplasmic pGSK-3β trended toward greater OS with GE treatment.
Conclusions
OS, PFS, QOL, and RR were comparable between arms. Adding E to G did not increase hematologic toxicities. GE does not warrant further investigation in unselected pancreatic cancer patients.
Often the topic is the subject of considerable ongoing investigation. ...the reader should view the ECD as the best attempt of the ACCF and document cosponsors to inform and guide clinical practice ...in areas where rigorous evidence may not yet be available or evidence to date is not widely applied to clinical practice. All participating organizations participated in peer review, resulting in 22 reviewers representing 170 comments.\n Anderson Content Reviewer--ACCF Unstable Angina Guideline BSCI/sanofi None None AstraZeneca (DSMB) Gilead Pharma (DSMB) Hamilton Health Sciences University (DSMB) Harvard (DSMB) NIH (DSMB) Toshiba Deseret Foundation, Intermountain Healthcare NIH Defendant, management of cardiopulmonary arrest post-op, 2010 Defendant, stroke after ablation for AF, 2010 James A. de Lemos Content Reviewer--ACCF Task Force on CECD Johnson & Johnson Tethys Bristol-Myers Squibb/sanofi-aventis partnership* None Bristol-Myers Squibb (DSMB) Roche Diagnostics* AstraZeneca* Daiichi Sankyo None Robert A. Guyton Content Reviewer--ACCF CABG Guideline None None None Edwards Lifesciences NIH None None Richard J. Kovacs Content Reviewer--ACCF Abbott Laboratories Biomedical Systems Cook* ECG Scanning and Medical Services* Eli Lilly* Endocyte Essentialis XenoPort None None None None None Frederick G. Kushner Content Reviewer--ACCF STEMI Guideline FDA None Bristol-Myers Squibb Merck Roche Holding* Daiichi Sankyo Hoffmann La Roche NIH Novartis FDA Science Board None David Lanfear Content Reviewer--ACCF Heart Failure and Transplant Committee Thoratec None None sanofi-aventis* Johnson & Johnson* HFSA None John F. Robb Content Reviewer--ACCF None None None None None None Sidney C. Smith, Jr. Relationships in this table are modest unless otherwise noted.AACC = American Association for Clinical Chemistry; ACCF = American College of Cardiology Foundation; ACCP = American College of Chest Physicians; ACP = American College of Physicians; AF = atrial fibrillation; AHA = American Heart Association; CABG = coronary artery bypass graft surgery; CECD = Clinical Expert Consensus Documents; DSMB = Data and Safety Monitoring Board; FDA = Food and Drug Administration; HFSA = Heart Failure Society of America; NIH = National Institutes of Health; PCI = percutaneous coronary intervention; SCAI = Society for Cardiovascular Angiography and Interventions; STEMI = ST-segment elevation myocardial infarction; UA = unstable angina.
This study sought to determine the impact of surgical myectomy on long-term survival in hypertrophic cardiomyopathy (HCM).
Left ventricular (LV) outflow tract obstruction in HCM increases the ...likelihood of heart failure and cardiovascular death. Although surgical myectomy is the primary treatment for amelioration of outflow obstruction and advanced drug-refractory heart failure symptoms, its impact on long-term survival remains unresolved.
Total and HCM-related mortality were compared in three subgroups comprised of 1,337 consecutive HCM patients evaluated from 1983 to 2001: 1) surgical myectomy (n = 289); 2) LV outflow obstruction without operation (n = 228); and 3) nonobstructive (n = 820). Mean follow-up duration was 6 ± 6 years.
Including two operative deaths (procedural mortality, 0.8%), 1-, 5-, and 10-year overall survival after myectomy was 98%, 96%, and 83%, respectively, and did not differ from that of the general U.S. population matched for age and gender (p = 0.2) nor from patients with nonobstructive HCM (p = 0.8). Compared to nonoperated obstructive HCM patients, myectomy patients experienced superior survival free from all-cause mortality (98%, 96%, and 83% vs. 90%, 79%, and 61%, respectively; p < 0.001), HCM-related mortality (99%, 98%, and 95% vs. 94%, 89%, and 73%, respectively; p < 0.001), and sudden cardiac death (100%, 99%, and 99% vs. 97%, 93%, and 89%, respectively; p = 0.003). Multivariate analysis showed myectomy to have a strong, independent association with survival (hazard ratio 0.43; p < 0.001).
Surgical myectomy performed to relieve outflow obstruction and severe symptoms in HCM was associated with long-term survival equivalent to that of the general population, and superior to obstructive HCM without operation. In this retrospective study, septal myectomy seems to reduce mortality risk in severely symptomatic patients with obstructive HCM.
Obesity is a risk factor for atrial fibrillation and other cardiovascular conditions. Our objective was to determine whether catheter-based ablation effectively treated atrial fibrillation in obese ...patients.
Five hundred twenty-three consecutive patients with symptomatic, medication-refractory atrial fibrillation underwent catheter ablation. Patients were grouped by body mass index (lean, < 25 kg/m(2); overweight, 25 to 29.9 kg/m(2); obese, > or = 30 kg/m(2)). Outcome and quality of life were measured with a general health survey (Medical Outcomes Study 36-item Short-Form General Health Survey SF-36); patients were assessed before ablation and at 3 and 12 months after the procedure. Two hundred twenty-eight study patients (44%) were overweight, and 201 (38%) were obese. Twelve months after curative ablation, 72% of patients were free of atrial fibrillation without the use of antiarrhythmic agents; 84% were arrhythmia free when those receiving medication were included. Atrial fibrillation was eliminated in 75%, 72%, and 70% of the lean, overweight, and obese patients, respectively, at 12 months (P=0.41, trend test). SF-36 scores were lower for patients with higher body mass index (P<0.05) at baseline. SF-36 scores improved in every functional domain for all body mass index groups after ablation. The mean SF-36 total physical score increased from 59+/-20 at baseline to 77+/-19 in 12 months (P<0.001). The total mental health score improved from 66+/-18 to 79+/-16 in 12 months (P<0.001).
Catheter ablation of atrial fibrillation was effective in obese patients. Coexistence of atrial fibrillation and obesity indicated lower SF-36 scores, but the improvement in quality of life was consistent across all body mass index categories.
This advisory summarizes the current database on pacing modalities and algorithms used to prevent and terminate atrial fibrillation (AF). On the basis of the evidence indicating that ventricular ...pacing is associated with a higher incidence of AF in patients with sinus node dysfunction, a patient who has a history of AF and needs a pacemaker for bradycardia should receive a physiological pacemaker (dual chamber or atrial) rather than a single-chamber ventricular pacemaker. For patients who need a dual-chamber pacemaker, efforts should be made to program the device to minimize the amount of ventricular pacing when atrioventricular conduction is intact. Many pacemakers and implantable defibrillators have features designed to prevent AF and to terminate AF with rapid atrial pacing. The evidence to support their use is limited, although these algorithms appear to be safe and usually add little additional cost. For patients who have a bradycardia indication for pacing and also have AF, no consistent data from large randomized trials support the use of alternative single-site atrial pacing, multisite right atrial pacing, biatrial pacing, overdrive pacing, or antitachycardia atrial pacing. Even fewer data support the use of atrial pacing in the management of AF in patients without symptomatic bradycardia. At present, permanent pacing to prevent AF is not indicated; however, additional studies are ongoing, which will help to clarify the role of permanent pacing for AF.
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