Phase II trial of continuous low-dose temozolomide for patients with recurrent malignant glioma

Background In this phase II trial, we investigated the efficacy of a metronomic temozolomide schedule in the treatment of recurrent malignant gliomas (MGs).

Methods Eligible patients received daily temozolomide (50 mg/m2) continuously until progression. The primary endpoint was progression-free survival rate at 6 months in the glioblastoma cohort (N = 37). In an exploratory analysis, 10 additional recurrent grade III MG patients were enrolled. Correlative studies included evaluation of 76 frequent mutations in glioblastoma (iPLEX assay, Sequenom) aiming at establishing the frequency of potentially “drugable” mutations in patients entering recurrent MG clinical trials.

Results Among glioblastoma patients, median age was 56 y; median Karnofsky Performance Score (KPS) was 80; 62% of patients had been treated for ≥2 recurrences, including 49% of patients having failed bevacizumab. Treatment was well tolerated; clinical benefit (complete response + partial response + stable disease) was seen in 10 (36%) patients. Progression-free survival rate at 6 months was 19% and median overall survival was 7 months. Patients with previous bevacizumab exposure survived significantly less than bevacizumab-naive patients (median overall survival: 4.3 mo vs 13 mo; hazard ratio = 3.2; P = .001), but those patients had lower KPS (P = .04) and higher number of recurrences (P < .0001). Mutations were found in 13 of the 38 MGs tested, including mutations of EGFR (N = 10), IDH1 (N = 5), and ERBB2 (N = 1).

Conclusions In spite of a heavily pretreated population, including nearly half of patients having failed bevacizumab, the primary endpoint was met, suggesting that this regimen deserves further investigation. Results in bevacizumab-naive patients seemed particularly favorable, while results in bevacizumab-failing patients highlight the need to develop further treatment strategies for advanced MG.

Is chemotherapy dose intensity adequate in breast cancer management in the Australian healthcare setting: a retrospective analysis

Aim
To determine the adequacy of chemotherapy received dose intensity (RDI) in breast cancer treatment in a general population and to identify factors that influence RDI.

Methods
A retrospective analysis of breast cancer patients who commenced a course of i.v. chemotherapy in 2008 was undertaken. Data were collected on patient and tumor characteristics, chemotherapy regimen, dose (including delays, reductions and the reasons for these), granulocyte colony-stimulating factor (G-CSF) use and febrile neutropenia incidence. RDI was calculated using the planned and actual dose received and time taken. A level of ≥85% RDI was considered acceptable for treatment given with curative intent.

Results
In all, 131 patients (aged 28 to 77 years) received chemotherapy in adjuvant (n = 76, 58%), neoadjuvant (n = 11, 8%) and metastatic settings (n = 44, 34%). RDI did not reach 85% for 12% adjuvant, 36% neoadjuvant and 34% metastatic cases (χ2 = 10.55, P = 0.005). Overall, 43% of patients received G-CSF.

Conclusion
Acceptable chemotherapy RDI was delivered for most patients in the adjuvant setting but not in the neoadjuvant setting. G-CSF treatment contributed to the optimization of dose intensity in the adjuvant setting only. Dose intensity in the metastatic setting was considered satisfactory where quality of life is the primary focus. Other factors can be modified to improve RDI.

Dose-dependent increases in heart rate variability and arterial compliance in overweight and obese adults with DHA-rich fish oil supplementation

Heart rate (HR) variability and large arterial compliance can be improved using fish oils. DHA, a component of fish oil, has cardiovascular health benefits, but its effect on HR variability (HRV) and arterial compliance is yet to be quantified. Sixty-seven overweight or obese adults (thirty-six males and thirty-one females; 53 (sem 2) year; BMI 31·7 (sem 1·1) kg/m²) were randomly allocated to consume either 6 g/d sunola oil (control; n 17), fish oil (260 mg DHA+60 mg EPA per g) at doses of 2 g/d (n 16), 4 g/d (n 17) or 6 g/d (n 17). Blood pressure, HR and compliance of large and small arteries were measured while supine at baseline and after 12 weeks in all participants, and HRV was assessed in a subgroup of forty-six participants. There was no effect of fish oil on blood pressure, small artery compliance or HR. However, the low frequency:high frequency ratio of HRV decreased with increasing doses of fish oil (r − 0·34, P = 0·02), while large artery compliance increased (r 0·34, P = 0·006). Moreover, the changes in these biomarkers were significantly correlated (r − 0·31, P = 0·04) and may reflect fish oil-induced improvements in arterial function and cardiac autonomic regulation.

Dose-dependent effects of docosahexaenoic acid-rich fish oil on erythrocyte docosahexaenoic acid and blood lipid levels

Consumption of long-chain n-3 PUFA, particularly DHA, has been shown to improve cardiovascular risk factors but the intake required to achieve benefits is unclear. We sought to determine the relationship between DHA intake, increases in erythrocyte DHA content and changes in blood lipids. A total of sixty-seven subjects (thirty-six male, thirty-one female, mean age 53 years) with fasting serum TAG ≥ 1·1 mmol/l and BMI>25 kg/m² completed a 12-week, randomized, double-blind, placebo-controlled parallel intervention. Subjects consumed 2, 4 or 6 g/d of DHA-rich fish oil (26 % DHA, 6 % EPA) or a placebo (Sunola oil). Fasting blood lipid concentrations and fatty acid profiles in erythrocyte membranes were assessed at baseline and after 6 and 12 weeks. For every 1 g/d increase in DHA intake, there was a 23 % reduction in TAG (mean baseline concentration 1·9 (sem 0·1) mmol/l), 4·4 % increase in HDL-cholesterol and 7·1 % increase in LDL-cholesterol. Erythrocyte DHA content increased in proportion to the dose of DHA consumed (r 0·72, P < 0·001) and the increase after 12 weeks was linearly related to reductions in TAG (r − 0·38, P < 0·01) and increases in total cholesterol (r 0·39, P < 0·01), LDL-cholesterol (r 0·33, P < 0·01) and HDL-cholesterol (r 0·30, P = 0·02). The close association between incorporation of DHA in erythrocytes and its effects on serum lipids highlights the importance of erythrocyte DHA as an indicator of cardiovascular health status.

The cost-effectiveness of the Dose Adjustment for Normal Eating (DAFNE) structured education programme: an update using the Sheffield Type 1 Diabetes policy model

AIMS: 
To estimate the cost-effectiveness of training in flexible intensive insulin therapy [as provided in the Dose Adjustment for Normal Eating (DAFNE) structured education programme] compared with no training for adults with Type 1 diabetes mellitus in the UK using the Sheffield Type 1 Diabetes Policy Model.

METHODS: 
The Sheffield Type 1 Diabetes Policy Model was used to simulate the development of long-term microvascular and macrovascular diabetes-related complications and the occurrence of diabetes-related adverse events in 5000 adults with Type 1 diabetes. Total costs and quality-adjusted life years were estimated from a National Health Service perspective over a lifetime horizon, discounted at a rate of 3.5%. The treatment effectiveness of DAFNE was modelled as a reduction in HbA1c that affected the risk of developing long-term diabetes-related complications. Probabilistic and structural sensitivity analyses were conducted.

RESULTS:
DAFNE resulted in greater life expectancy and reduced incidence of some diabetes-related complications compared with no DAFNE. DAFNE was found to generate an average of 0.0294 additional quality-adjusted life years for an additional cost of £426 per patient, leading to an incremental cost-effectiveness ratio of £14 400 compared with no DAFNE. There was a 54% probability that DAFNE would be cost-effective at a willingness-to-pay threshold of £20 000 per quality-adjusted life year.

CONCLUSIONS: 
The results of this study suggest that DAFNE is a cost-effective structured education programme for people with Type 1 diabetes and support its provision by the National Health Service in the UK.

Evaluating irradiation dose for sterility induction and quality control of mass-produced fruit fly Bactrocera tryoni (Diptera : Tephritidae)

The sterile insect technique has been routinely used to eradicate fruit fly Bactrocera tryoni (Froggatt) incursions. This study considers whether fly quality in a mass-rearing facility can be improved by reducing irradiation doses, without sacrificing reproductive sterility. Pupae were exposed to one of five target irradiation dose ranges: 0, 40-45, 50-55, 60-65, and 70-75 Gy. Pupae were then assessed using routine quality control measures: flight ability, sex ratio, longevity under nutritional stress, emergence, and reproductive sterility. Irradiation did not have a significant effect on flight ability or sex ratio tests. Longevity under nutritional stress was significantly increased at 70-75 Gy, but no other doses differed from 0 Gy. Emergence was slightly reduced in the 50-55, 60-65, and 70-75 Gy treatments, but 40-45 Gy treatments did not differ from 0 Gy, though confounding temporal factors complicate interpretation. Reproductive sterility remained acceptable (> 99.5%) for all doses--40-45 Gy (99.78%), 50-55 Gy (100%), 60-65 Gy (100%), and 70-75 Gy (99.99%). We recommend that B. tryoni used in sterile insect technique releases be irradiated at a target dose of 50-55 Gy, providing improved quality and undiminished sterility in comparison with the current 70-75 Gy standard while also providing a substantial buffer against risk of under dosing.

Toxicity and dose intensity of FOLFOX in patients with increased body mass index

This study was conducted at St James‘s Hospital, Dublin, Ireland, in 2010. It evaluated the dose intensity and toxicities experienced by patients of normal and increased body mass index treated with FOLFOX chemotherapy, and demonstrated that overweight patients may tolerate doses based on actual body weight.