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BACKGROUND: Results of previous randomised trials have shown that interventions that lower LDL cholesterol concentrations can significantly reduce the incidence of coronary heart disease (CHD) and other major vascular events in a wide range of individuals. But each separate trial has limited power to assess particular outcomes or particular categories of participant. METHODS: A prospective meta-analysis of data from 90,056 individuals in 14 randomised trials of statins was done. Weighted estimates were obtained of effects on different clinical outcomes per 1.0 mmol/L reduction in LDL cholesterol. FINDINGS: During a mean of 5 years, there were 8186 deaths, 14,348 individuals had major vascular events, and 5103 developed cancer. Mean LDL cholesterol differences at 1 year ranged from 0.35 mmol/L to 1.77 mmol/L (mean 1.09) in these trials. There was a 12% proportional reduction in all-cause mortality per mmol/L reduction in LDL cholesterol (rate ratio [RR] 0.88, 95% CI 0.84-0.91; p

We compared the results of randomised trials comparing taxane-containing chemotherapy regimens with regimens not containing a taxane in women with metastatic breast cancer. The specialised register of the Cochrane Breast Cancer Group was searched in March 2004. Eligibility was assessed and data extracted from eligible studies by two reviewers. Hazard ratios (HR) were derived for time-to-event outcomes, and a fixed-effect model was used for meta-analysis. Tumour response rates were analysed as dichotomous variables. Of 21 eligible trials, 16 had published some results and 12 data on overall survival. An estimated 2621 deaths among 3643 women suggest a significant difference in overall survival in favour of taxane-containing regimens (HR 0.93, 95% confidence interval (CI) 0.86–1.00, P=0.05). The treatment effect on survival was similar if only trials of first-line chemotherapy were included, although not statistically significant. There appeared to be an advantage for taxanes in time to progression (HR 0.92, 95% CI 0.85–0.99, P=0.02) and overall response (odds ratio (OR) 1.34, 95% CI 1.18–1.52, P

Aims We examined the clinical characteristics and outcome of patients with early ( 4h) presentation treated by primary angioplasty or thrombolytic therapy for acute myocardial infarction. Methods and Results We studied 2635 patients enrolled in 10 randomized trials of primary angioplasty (n=1302) vs thrombolytic therapy (n=1333) in acute myocardial infarction, and baseline characteristics of the two groups were comparable. Increase in presentation delay is associated with older age, female gender, diabetes and an increased heart rate. We classified the patients according to the time delay from symptom onset to presentation into three categories: early presentation (

Background: The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial was designed to exploit results from whole genome sequencing of pancreatic cancer collected under the auspices of the ICGC in Australia. Results showed that small subsets of patients had actionable changes in their tumor genome that could be druggable with currently available therapies. 93% of cases analyzed harbored a KRAS mutation, KRAS wildtype phenotype may enrich for susceptibility to EGFR inhibition. Her2 positivity occurs in 2% and may confer sensitivity to Her inhibition. Tumors displaying defects in the DNA damage repair pathway (∼5%) respond to DNA damaging chemotherapy. Trial design: The IMPaCT trial is a randomized phase 2 study of first line molecularly guided therapy against standard therapy with gemcitabine in advanced pancreas cancer. We screen potential patients for the three molecular targets: Her2 amplification: trastuzumab+gemcitabine; KRAS wildtype: erlotinib+gemcitabine; and DNA damage: mitomycin C+5-fluorouracil chemotherapy. If a patient's tumour has one of these signals, they consent to be randomized to precision treatment tailored for them or standard therapy with gemcitabine. For analysis, the precision treatment arm will be considered as a whole and compared to the standard therapy arm. In our initial cohort of patients who underwent resection with curative intent, 70% recurred. Recurrence occurred on average 16m after initial surgery. Collection of tissue commenced in 2009. The first site to open was in June 2013 by which time, only 6 patients for whom we had complete sequence data and actionable mutations were still alive, so we changed the trial to screen de novo metastatic patients. Using the WGS data, we constructed a custom sequencing panel for DNA extracted from FFPE core biopsies to screen for mutations in KRAS, BRCA2, BRCA1, PALB2 and ATM. Her2 screening is undertaken with IHC and FISH. We have screened 49 cases, and found 10 with relevant molecular targets, 5 of whom were eligible. The average time from biopsy to delivery of results is 23d, an amendment has allowed patients to commence standard therapy whilst waiting for the results of molecular analysis. The IMPaCT trial is breaking new ground in the treatment of pancreas cancer. Disclosure: All authors have declared no conflicts of interest.

We developed a prognostic strategy for quantifying the long-term risk of coronary heart disease (CHD) events in survivors of acute coronary syndromes (ACS).Strategies for quantifying long-term risk of CHD events have generally been confined to primary prevention settings. The Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study, which demonstrated that pravastatin reduces CHD events in ACS survivors with a broad range of cholesterol levels, enabled assessment of long-term prognosis in a secondary prevention setting.Based on outcomes in 8,557 patients in the LIPID study, a multivariate risk factor model was developed for prediction of CHD death or nonfatal myocardial infarction. Prognostic indexes were developed based on the model, and low-, medium-, high- and very high-risk groups were defined by categorizing the prognostic indexes.In addition to pravastatin treatment, the independently significant risk factors included: total and high density lipoprotein cholesterol, age, gender, smoking status, qualifying ACS, prior coronary revascularization, diabetes mellitus, hypertension and prior stroke. Pravastatin reduced coronary event rates in each risk level, and the relative risk reduction did not vary significantly between risk levels. The predicted five-year coronary event rates ranged from 5% to 19% for those assigned pravastatin and from 6.4% to 23.6% for those assigned placebo.Long-term prognosis of ACS survivors varied substantially according to conventional risk factor profile. Pravastatin reduced coronary risk within all risk levels; however, absolute risk remained high in treated patients with unfavorable profiles. Our risk stratification strategy enables identification of ACS survivors who remain at very high risk despite statin therapy.

Summary Background The LIPID study is a major trial of secondary prevention of coronary-heart-disease events that includes hospital admission with unstable angina (as well as myocardial infarction) as a qualifying event. In this substudy of LIPID, we compared subsequent cardiovascular risks and the effects of pravastatin in patients with previous unstable angina or previous myocardial infarction. Methods 3260 patients diagnosed with unstable angina and 5754 with acute myocardial infarction 3–36 months previously were randomly assigned 40 mg pravastatin daily or placebo over a mean of 6·0 years. The risk reduction of a range of cardiovascular events was estimated by means of the hazard ratio in Cox's proportional hazards model. Findings Among patients assigned placebo, survival in the two diagnosis groups was similar. The relative risk reduction for mortality with pravastatin was 20·6% in the myocardial infarction group and 26·3% in the unstable angina group (p=0·55). Pravastatin significantly reduced the rates of all prespecified coronary endpoints in the myocardial infarction group. In patients with previous unstable angina, coronary heart disease mortality, total mortality, myocardial infarction, a need for coronary revascularisation, the number of admissions to hospital, and the number of days in hospital were significantly lower with pravastatin. Overall, hospital admission for unstable angina was the most common endpoint (24·6% of the placebo group; 22·3% of the pravastatin group). Interpretation Patients who have survived acute myocardial infarction or unstable angina have a similar long-term prognosis, a high occurrence of subsequent unstable angina, and benefit similarly from therapy with pravastatin.

BACKGROUND: Several epidemiologic studies have concluded that there is no relation between total cholesterol levels and the risk of stroke. In some studies that classified strokes according to cause, there was an association between increasing cholesterol levels and the risk of ischemic stroke and a possible association between low cholesterol levels and the risk of hemorrhagic stroke. Recent reviews of trials of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors have suggested that these agents may reduce the risk of stroke. METHODS: In a double-blind trial (the Long-Term Intervention with Pravastatin in Ischaemic Disease study), we compared the effects of pravastatin on mortality due to coronary heart disease (the primary end point) with the effects of placebo among 9014 patients with a history of myocardial infarction or unstable angina and a total cholesterol level of 155 to 271 mg per deciliter (4.0 to 7.0 mmol per liter). Our goal in the present study was to assess effects on stroke from any cause and nonhemorrhagic stroke, which were secondary end points. RESULTS: There were 419 strokes among 373 patients over a follow-up period of six years. A total of 309 strokes were classified as ischemic, 31 as hemorrhagic, and 79 as of unknown type. Among the patients given placebo, the risk of stroke was 4.5 percent, as compared with 3.7 percent among those given pravastatin (relative reduction in risk, 19 percent; 95 percent confidence interval, 0 to 34 percent; P=0.05). Non-hemorrhagic stroke occurred in 4.4 percent of the patients given placebo, as compared with 3.4 percent of those given pravastatin (reduction in risk, 23 percent; 95 percent confidence interval, 5 to 38 percent; P=0.02). Pravastatin had no effect on hemorrhagic stroke (incidence, 0.2 percent in the placebo group vs. 0.4 percent in the pravastatin group; P=0.28). CONCLUSIONS: Pravastatin has a moderate effect in reducing the risk of stroke from any cause and the risk of nonhemorrhagic stroke in patients with previous myocardial infarction or unstable angina.

OBJECTIVE: To investigate the psychometric properties of a cardiovascular extension of an existing utility-based quality of life questionnaire (Health Measurement Questionnaire). The new instrument has been named the Utility Based Quality of life--Heart questionnaire, or UBQ-H. DESIGN: Explored the test-retest reliability, construct validity, and responsiveness of the UBQ-H. PATIENTS: A sample of 322 patients attending cardiac outpatient clinics were recruited from two large metropolitan teaching hospitals. A second sample of 1112 patients taking part in the LIPID trial was also used to investigate the validity and responsiveness of the UBQ-H. RESULTS: Ninety per cent of all UBQ-H questionnaires were returned, and item completion rates were high (median of less than 1% missing or N/A answers). Cronbach's alpha measure of internal consistency for the scales ranged between 0.79- 0.91, and each item was also most strongly correlated with its hypothesised domain than alternative domains. The intra-class test- retest reliability of the UBQ-H scales ranged from 0.65 to 0.81 for patients with stable health. Results supported the construct validity of the UBQ-H. The UBQ-H was significantly correlated with other information on quality of life (for example, General Health Questionnaire) as anticipated. The instrument was able to distinguish between contrasted groups of patients (for example, with versus without symptoms of dyspnoea, prior myocardial infarction versus none, etc), and was responsive to changes in health associated with adverse events requiring hospitalisation. CONCLUSIONS: The modifications made to the Health Measurement Questionnaire has resulted in an assessment designed for cardiovascular patients that has proved to be both reliable and valid.

We have intermixed GaAs/(AlGa)As multiquantum structures for waveguides and lasers by 3 MeV Ar implantation and 850 °C, 30 min closed‐tube annealing. Buried‐heterostructure lasers defined by Ar mixing had threshold currents of 100 mA for 370‐μm‐long devices. As waveguides for 1.15 μm light, the devices exhibited losses of 25 cm−1 in the annealed, implanted regions, and 15 cm−1 in unimplanted regions defined by adjacent implants. Analysis of the results illustrates important considerations for implant mixing for waveguide formation.

An asymmetric Fabry–Perot structure with a multiple quantum well active region is demonstrated to provide a reflection change of >45% for an operating voltage swing of only ∼2 V, with a contrast ratio of more than 15. Photocurrent measurements show that the same devices also work as voltage‐tunable detectors. Such devices compete effectively with low‐voltage waveguide modulators, with further advantages of easy coupling and compact sizes, i.e., small capacitances.

The patterns of revascularisation with percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) surgery in the GUSTO 1 trial patients in Australia are described. In comparison with rates documented in earlier trials of thrombolytic therapy in Australia, the rates of revascularisation post-thrombolysis increased by 50%, primarily due to a doubling in the rate of use of PTCA. However, the rates were low by international comparisons. There were marked variations in the rates of revascularisation between States, but no correlation with differences in mortality between States. The main predictors of post thrombolysis PTCA were prior angina, mild infarction and access to PTCA facilities.

One way of examining trade-offs between quantity and quality of life (QOL) is to combine them into a single measure such as quality-adjusted life year (QALY). If censoring occurs, then estimation presents some difficulties. One approach, known as Q-TWiST, is to define a series of health states, use a 'partitioned' survival analysis to calculate the average time in each state, and then weight each state according to its quality of life to calculate QALYs. Such health-state models, however, are unhelpful when the transitions between health states are unclear or if they do not adequately reflect variations in quality of life. We therefore examine an alternative analysis to be used when repeated measures of quality of life are available from individual patients in a clinical trial. The method proceeds by separating quality of life and survival, that is, dQALY/dt = S(t)Q(t), where S(t) is the survival curve, estimated from the standard Kaplan-Meier method, and Q(t) is the quality of life function, derived from individual repeated measures of quality of life. We derive single health-state (QALY) and multiple health-state (Q-TWiST) models and illustrate the approach by comparing different durations of adjuvant chemotherapy for breast cancer.

We sought to show that hirudin might interact differently with streptokinase (SK) and tissue-type plasminogen activator (t-PA), which could reduce the incidence of death or reinfarction at 30 days.In a large-scale trial of patients with acute coronary syndromes, hirudin provided modest benefit compared with heparin. However, the interaction with thrombolytic agents was not specifically assessed.Patients with symptoms of acute myocardial infarction and electrocardiographic ST segment elevation were treated with thrombolytic therapy and randomly assigned to receive hirudin or heparin.A total of 2,274 patients received t-PA, and 1,015 received SK. Baseline characteristics were balanced by antithrombin assignment. Among SK-treated patients, death or reinfarction at 30 days occurred more often in those treated with adjunctive heparin (14.4%) rather than hirudin (8.6%, odds ratio [OR] 1.78, 95% confidence interval [CI] 1.20 to 2.66, p = 0.004). Among t-PA-treated patients, the rates were 10.9% with heparin and 10.3% with hirudin (OR 1.06, 95% CI 0.81 to 1.38, p = 0.68; for treatment heterogeneity: chi-square 4.20, degrees of freedom [df] 1, p = 0.04). After adjustment for baseline differences between thrombolytic groups, the rates were 9.1% for SK with hirudin, 10.3% for t-PA with hirudin, 10.5% for t-PA with heparin and 14.9% for SK with heparin (for treatment heterogeneity: chi-square 4.5, df 1, p = 0.03), suggesting that the beneficial treatment effect of hirudin was limited to the SK-treated patients.Hirudin interacts favorably with SK but not t-PA, highlighting the importance of thrombin activity after SK therapy and the potential for simulating the effects of a more potent fibrinolytic agent through direct antithrombin therapy.

Missing information on quality of life (QOL) is a significant problem in many cancer trials particularly for patients with advanced disease, where clinical deterioration may be a reason for not responding to quality of life assessments. Examples from four clinical trials are presented where non-respondents to quality of life assessments have poorer health than respondents. In this context, auxiliary outcome variables, such as health status, may be useful proxies in assessing the impact of missing QOL data on estimated treatment effects. This approach is illustrated in a trial of palliative treatment in advanced cancer. A method for imputation of missing QOL data based on auxiliary outcome variables is also illustrated. However, the most effective method of minimizing the problem of missing data is in designing the trial with preventative strategies in place. Since some missing data due to deteriorating health may still occur, the design should include the collection of auxiliary QOL information. Preventative strategies are illustrated with an ongoing trial in advanced breast cancer.

The Long-term Intervention with Pravastatin in Ischemic Heart Disease (LIPID) trial is a double-blind, randomized, placebo-controlled trial evaluating the long-term effect of pravastatin on coronary mortality in patients with a previous myocardial infarction or unstable angina-ischemic heart disease (IHD). It is planned to run for at least five years with 9014 patients from 85 centers in Australia and New Zealand. The trial will monitor cause-specific mortality and major clinical events associated with each treatment. Running in parallel with the main study is a prospective economic analysis, the objectives of which are (1) to estimate the effectiveness of pravastatin compared with placebo in terms of survival, quality of life (QOL), and quality-adjusted life-years (QALY); (2) to estimate the resource usage associated with pravastatin compared with placebo-in particular, to study whether it alters resource usage through prevention of disease progression; and (3) to use this information for a cost-utility analysis with cost per quality-adjusted life-year as the unit of analysis. A novel aspect of the design is the use of a preliminary cost-effectiveness analysis, based on "best-guess" values, and a sensitivity analysis over plausible ranges to guide the choice of subsample size. Some data, such a mortality, days spent in hospital, major clinical events, and drug use, are being collected within the main LIPID trial. However, additional subsamples for the cost-effectiveness study will include information on quality of life, time off work, and resources used, such as time in hospital, procedures, and medications taken. The methods and sample sizes for these substudies have been a crucial issue in validity and feasibility.

We developed a logistic regression model with data from the GUSTO-I trial to predict mortality rate differences in individual patients who received accelerated tissue plasminogen activator (TPA) versus streptokinase treatment for acute myocardial infarction. A nomogram was developed from a reduced version of this model that approximated the underlying risk of patients treated with streptokinase, and thus the benefit of TPA. The 30-day mortality rate with accelerated TPA was 0.063 versus 0.073 with streptokinase and subcutaneously administered heparin and 0.074 with streptokinase and intravenously administered heparin. No baseline patient characteristics were significantly associated with a different relative effect of TPA. Older patients and those with anterior infarction, higher Killip classification (except Killip class IV), lower blood pressure, and increased heart rate had the greatest absolute benefit with accelerated TPA. Patients with acute myocardial infarction who had more high-risk characteristics derived a greater absolute benefit from treatment with accelerated TPA versus streptokinase.

To investigate the effect of two doses of megestrol acetate (MA) compared with placebo on quality of life (QoL) and nutritional status (NS) in patients with advanced endocrine-insensitive cancer.Two hundred forty patients were randomised to double-blind MA 480 mg/day, MA 160 mg/day, or matching placebo for 12 weeks. Nutritional status (including weight, skinfold thickness and midarm circumference) and QoL (using 6 linear analogue self-assessment (LASA) scales) were assessed at randomisation and after four, eight and 12 weeks. A QoL ranking incorporating QoL and death was also used ranging from 1 = dead to 5 = much better QoL.One hundred seventy-four patients were assessable at week four, 136 at week eight and 103 patients at week 12. Patients receiving MA reported substantially better appetite (P = 0.001), mood (P = 0.001) and overall quality of life (P0.001), and possibly less nausea and vomiting (P = 0.08) than patients receiving placebo, based on a test for trend. A larger benefit was seen with the higher dose which (unlike the lower dose) was significantly better in pairwise comparisons with placebo for appetite, mood and overall QoL (each Por = 0.001). Despite some missing data on QoL scores, QoL ranking was available on 227 (95%) of patients with significantly higher QoL ranking associated with MA (P = 0.002). Improvements in QoL occurred early within four weeks and were sustained. No statistically significant differences were observed in NS measurements, including weight (P = 0.29). Side effects of therapy were minor and did not differ significantly across treatments.Megestrol acetate given at 480 mg/day is useful palliation in patients with endocrine-insensitive advanced cancer. It improves appetite, mood and overall quality of life in these patients, although not through a direct effect on nutritional status.

Elderly patients with acute myocardial infarction have much to gain from reperfusion with thrombolytic therapy but are also at increased risk of adverse events. We examined outcomes according to age of patients receiving thrombolysis in an international trial.Patients were randomized to streptokinase plus subcutaneous heparin, streptokinase plus intravenous heparin, accelerated tissue plasminogen activator (TPA) plus intravenous heparin, or streptokinase and TPA plus intravenous heparin. Clinical outcomes at 30 days (death, stroke, and nonfatal, disabling stroke) and 1-year mortality were summarized descriptively for patients aged65 (n = 24,708), 65 to 74 (n = 11,201), 75 to 85 (n = 4625), and85 years (n = 412) and assessed as continuous functions of age. Older patients had a higher-risk profile with regard to baseline clinical and angiographic characteristics. Mortality at 30 days increased markedly with age (3.0%, 9.5%, 19.6%, and 30.3% in the four groups, respectively), as did stroke, cardiogenic shock, bleeding, and reinfarction. Combined death or disabling stroke occurred less often with accelerated TPA in all but the oldest patients, who showed a weak trend toward a lower incidence with streptokinase plus subcutaneous heparin: odds ratio 1.13; 95% confidence interval 0.6, 2.1. Similarly, accelerated TPA treatment resulted in lower 1-year mortality in all but the oldest patients (47% TPA versus 40.3% streptokinase).Lower mortality and greater net clinical benefit were seen with accelerated TPA in patients agedor = 85 years. Because data are limited for patients aged85 years, the relative superiority of a given thrombolytic regimen cannot be determined. The interactions of stroke and mortality with newer thrombolytic strategies must be examined explicitly in older patients.

Background The tumour suppressor gene PTEN may have a role as a biomarker for anti-EGFR therapy in CRC. As PTEN expression also has a relationship with VEGF expression via HIF-1 alpha, and the PI3K/mTOR pathways, we have explored the potential that PTEN loss may be predictive of outcome with an anti-VEGF agent. We also assess the prognostic value of PTEN as this remains controversial. Methods Patients enrolled in the Phase III MAX trial of capecitabine (C) +/- bevacizumab (B) (+/- mitomycin C (M)) with available tissues were analysed for PTEN expression (loss v no loss) as assessed using a Taqman® copy number assay to measure copy number variation at the PTEN locus. The predictive value of PTEN status for bevacizumab efficacy was examined. PTEN status was also correlated with progression-free survival (PFS) and overall survival (OS) outcomes, and a second sub analysis grouping PTEN by KRAS/BRAF status was also performed. Results Of the original 471 patients enrolled in the trial, tissues from 302 (64.1%) patients were analysed. Baseline characteristics of those with and without tissues were comparable. PTEN loss was observed in 38.7% of patients. There was no relationship between PTEN loss and KRAS or BRAF mutation (KRAS/BRAF MT v WT with PTEN loss; 34%/37% v 41%/39% respectively). PTEN loss was associated with rectal primary (p = 0.01) and lower rates of lung metastasis (p = 0.03). By using the comparison of C v CB + CBM, PTEN status was not significantly predictive of the effectiveness of B for PFS or OS (Table). PTEN status is also not prognostic for PFS or OS in multivariate analyses adjusting for other baseline factors (Loss v No Loss PFS HR 0.9 (0.7-1.16), OS HR 1.04 (0.79-1.38)). PTEN was also not prognostic when assessed by KRAS and BRAF status. Conclusions PTEN status did not significantly predict different benefit with anti-VEGF therapy. PTEN status was not prognostic for survival in advanced colorectal cancer. C vs CB + CBM Loss No loss P value (for interaction) PFS HR 0.51 0.33 - 0.79 HR 0.72 0.52-0.98 P = .26 OS HR 0.75 0.47-1.19 HR 1.00 0.70-1.43 P = .35 Disclosure T. Price: Uncompensated Advisory board Merck, AMGEN and Roche.Travel grants Merck and AMGEN. N. Tebbutt: Uncompensated Ad board Roche. All other authors have declared no conflicts of interest.

Background Cardiac toxicity (CT) is an uncommon but potentially fatal side effect of FP. The incidence of further CT if the same chemotherapy is continued is reported to be 20%*. Management of these patients remains poorly defined and options include continuing same dose/schedule of FP, adding a nitrate and calcium antagonist, switching administration schedule of FP, or substituting with raltitrexed, the later based primarily on case reports. Methods AGITG and OCTO (Oncology Clinical Trials Office – Oxford) members identified patients who had CT from FP, and were subsequently switched to raltitrexed. CT included angina, myocardial infarct (MI) or arrhythmia. A coronary angiogram was not mandatory. Results 42 patients were included in this clinical audit. Cancer diagnoses included colorectal (39pts), oesophageal (2) and ampullary carcinoma (1). Median age - 62 years (range 36-81). 27 patients (64%) were male. Median number of cycles prior to switching to raltitrexed was 2 (range 1-11). FP regimens included FOLFOX, CAPOX, continuous infusion 5FU, ECF, capecitabine alone. 40 patients had angina, 5 MI, and 2 arrhythmia with some patients experiencing >1 event at that time. 8 patients experienced two separate CT events, and 2 had 3 events prior to switching to raltitrexed. Following CT, 9 patients received raltitrexed alone, 32 received raltitrexed in combination with other agents or radiotherapy and one received raltitrexed alone followed by combination. Median number of raltitrexed cycles was 6 (range 1-21). One patient (CT rate 2.4%, 95% CI: 0.1-12.3) experienced a potentially related cardiac event (acute arrhythmia 5 mths into therapy) after switching to raltitrexed, a CT rate significantly lower than the 20% reported when continuing FP (exact binomial test p = 0.004). Conclusion The rate of recurrent CT after switching from FP to raltitrexed was low. The strategy of switching to raltitrexed may represent an acceptable option for patients that are deriving a benefit from FP based chemotherapy but in whom cardiac toxicity is a concern. (* Jensen SA et al. Cancer Chemotherapy & Pharm. 58:487-93, 2006). Disclosure D. Ransom: Unrestricted research grant from Astra Zeneca. All other authors have declared no conflicts of interest.

Background Glioblastoma (GBM) is the most aggressive malignant glial tumor. There is no accepted standard management after disease progression. Much remains unknown about the optimal use of bevacizumab (bev), including the role of continuing beyond progression, and patterns of radiological progression during and after use. In addition, the new Response Assessment in Neuro-Oncology (RANO) criteria have yet to be validated prospectively. Methods This study is a multi-centre, stratified randomised phase II trial. Patients have recurrent GBM after radiotherapy and temozolomide, have had no other chemotherapy for GBM, and have ECOG performance status 0–2. At least three months have elapsed since radiotherapy. In Part 1, patients are randomised 1:1 to intravenous bev 10 mg/kg 2-weekly and carboplatin AUC5 4-weekly or bev monotherapy. On progression, eligible patients are randomised to continue or cease bev (Part 2). The primary objective is to determine the effect of bev plus carboplatin versus bev alone on progression-free survival according to modified RANO criteria. Secondary endpoints are response rates, cognitive function, quality of life, steroid dose, toxicity, and overall survival. CogState, a validated neurocognitive testing system, is being used prospectively for the first time in this population and compared with mini-mental state examination. Exploratory endpoints include biomarker analyses, comparison of modified RANO and modified MacDonald criteria, predictive value of early MRI after 2 doses of bev, steroid dosing, and location and type of radiological progression during and after therapy. Results Enrolment commenced in Nov 2010, completing Part 1 accrual in Mar 2012 with 122 patients randomised from 17 Australian sites. Randomisation to Part 2 continues. Feasibility and safety data will be presented; efficacy outcome results are not expected until 2013. Conclusions The study results will significantly improve knowledge regarding the use of bevacizumab in the setting of recurrent GBM, as well as providing for the first time a prospective analysis of CogState neurocognitive testing for patients with brain tumours. Disclosure M.A. Rosenthal: Roche Advisory Board member. H. Wheeler: Roche Advisory Board member. E. Hovey: Roche Advisory Board member. A.K. Nowak: Roche Advisory Board member and has received research funding through Roche Australia. R.J. Simes: Roche Advisory Board Member. All other authors have declared no conflicts of interest.

To assess and compare quality of life of patients six months after an acute myocardial infarction treated with one of two thrombolytic agents, streptokinase (SK) or recombinant tissue plasminogen activator (tPA).A cohort study of consecutive patients randomly allocated to thrombolytic therapy and treated in hospitals participating in the Australian arm of the International tPA/SK Mortality Trial (AUS-TASK).776 patients with acute myocardial infarction were asked to complete questionnaires at their follow-up clinic visit six months after the infarct.Two measures were used: (i) the York Health Measurement Questionnaire, which measures activities and distress and provides basic descriptors of quality of life; and (ii) a time trade-off question about the number of years a person would be willing to give up in exchange for returning to full health.The quality of life of the 714 respondents (92%) was generally high, with a mean index of 0.98. The five main areas causing distress were: lack of energy; breathlessness; anxiety; difficulty sleeping; and pain. In the time trade-off question, the mean number of years respondents were willing to forgo, out of 15 years, was 0.87 years; while 76% did not think it worthwhile to forgo any time. The 8% of patients who declined to answer the questionnaire were in significantly poorer health (New York Heart Association classification, P = 0.01; and Karnofsky index, P0.001). There were no significant differences in quality of life or time trade-off answers between patients allocated to streptokinase or tPA (P = 0.96 and 0.73, respectively).Quality of life six months after myocardial infarction is generally high, and most patients are able to return to normal activities. However, it is significantly impaired in a small group of patients, mainly those with a subsequent stroke or re-infarction. There was no significant difference in quality of life between those treated with tPA and those with streptokinase.

Common methods of treatment allocation for multi-centre and/or stratified randomized clinical trials can result in substantial differences between the number of patients allocated to each treatment arm. This can occur in the overall trial for a permuted block design or within individual institutions/strata when using a minimization scheme. This may lead to a bias in the result. Also, these procedures can be predictable, with the possibility of an investigator-introduced selection bias. An easily implemented method of randomization is proposed which attempts to overcome these problems by balancing treatment allocations both within strata and across the trial as a whole. The method keeps a running tally on total treatment allocation numbers at all stratification levels. When a patient accrues a hierarchical decision rule is applied, and the allocation is deterministic if certain pre-defined limits are exceeded, and random otherwise. The method is an extension of the big stick design of Soares and Wu, and is related to both Zelen's key number randomization methods and the schemes of Nordle and Brantmark. Simulation studies are used to demonstrate that major imbalances possible with other schemes do not occur using this method, and that the potential for selection bias is much reduced.

PROBLEM: It remains unclear whether maternal immunization with paternal lymphocytes prior to conception improves the reproductive outcome in women with recurrent abortion in whom all secondary causes have been excluded. METHOD: A double-blind placebo controlled trial was instituted in women with unexplained recurrent spontaneous abortion, comparing immunization with 400 million paternal to 400 million maternal (autologous) lymphocytes. The groups were compared in a paired sequential trials chart, by logistic regression, and, in addition, a meta-analysis of this and other published trials was carried out. RESULTS: The live birth rate among pregnancies in paired couples with paternal lymphocyte immunization was 68% compared to 47% in the women who received their own cells. The results bordered on, but did not achieve, statistical significance. The women in each group were thoroughly investigated to exclude known causes of recurrent pregnancy loss and appeared to have been well matched in all variables. Women with lymphocytotoxic antibodies against paternal lymphocytes were excluded. Unlike our previous study there was not association between the time to conception and the chance of a successful outcome. Indeed, the time to conception was relatively short, 12 wk in all groups. The meta-analysis supported an overall modest favorable experience with paternal cells. CONCLUSION: The study is consistent with a general trend favoring paternal over maternal lymphocyte immunization but reinforces the need for larger multicenter controlled trials as well as more detailed biological study in humans to understand the nature of the maternal-fetal interface and its breakdown.

Two trials using ifosfamide-based combination chemotherapy for advanced soft-tissue sarcoma have been completed. In the first study, 50 evaluable patients received ifosfamide (5 g/m2) with mesna (5 g/m2) and doxorubicin (40 or 60 mg/m2) intravenously (i.v.) every 3 weeks. In all, 11 patients (22%) achieved an objective response [3 complete responses (CRs) and 8 partial responses (PRs)]. Toxicities included leukopenia, febrile neutropenia, nausea and vomiting, and alopecia. The overall median survival was 12 months. In the second study, 51 evaluable patients received ifosfamide (3 g/m2) with mesna (3 g/m2), both being given i.v. on day 1, together with etoposide (100 mg/m2) infused i.v. daily for 3 days. Six patients (12%) achieved objective responses (1 CR, 5 PRs). Toxicities included leukopenia, nausea and vomiting, and alopecia. The overall median survival was 7.4 months. Neither of these combination regimens appears to be more effective in advanced soft-tissue sarcoma than single-agent therapy with either ifosfamide or doxorubicin. If the results of chemotherapy in the management of these tumors are to be improved a new approach to therapy is clearly required.

5080 Background: In the CALYPSO trial, carboplatin (C)- pegylated liposomal doxorubicin (PLD) demonstrated superior therapeutic index versus C-paclitaxel (P) in recurrent ovarian cancer (ROC): ≥ 6 ...

9039 Background: Psychological responses to cancer are widely believed to affect survival. We investigated associations between hope, optimism, anxiety, depression, utility and survival in patients...

Clinical trials of adjuvant therapies usually measure the effectiveness of treatments by comparing disease-free survival or overall survival. These take into consideration only indirectly the quality of life experienced by the patients. We present some approaches that were developed to assess the impact of adjuvant therapy on the quality of life of breast cancer patients, as well as new methods created to compare treatments based on time spent without symptoms and toxicity (TWiST). The integration of these two methods (measuring quality and comparing duration of time) will provide a new tool for evaluating benefits from treatments given in the adjuvant setting.

4016 Background: Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), improves overall survival (OS) and progression free survival (PFS) in patients with K-ras WT chemotherapy refractory ACRC. Gene expression of the EGFR ligand epiregulin (EREG) may further predict benefit from cetuximab. Methods: CRC tumour samples were analyzed from a phase III clinical trial of cetuximab plus BSC vs BSC alone (NEJM 2007; 357(20)). EREG gene expression was detected in tumour-derived genomic RNA blinded to clinical outcome by quantitative real time-PCR. Using a pre-specified threshold for “high” EREG derived from a prior study (CA225–045), the predictive effect of (1) high vs low EREG among K-ras WT and (2) high EREG/K-ras WT status (“Combimarker”) versus all other patients on OS and PFS was examined using a Cox model with tests for treatment-biomarker interaction. Results: Both EREG gene expression levels and K-ras mutation status were ascertained in 385 (67%) of the total study population (193 cetuximab, 192 BSC). In the K-ras WT subset, OS was better for cetuximab than BSC among patients with high EREG (HR 0.43; p [Table: see text]

4616 Background: Our previous study of Gem with sandwich 5FU-3DRT for LAPC was encouraging (Br J Cancer 2007: 97, 464–471). Gem-Ox has higher response rate than Gem, improved progression free survival (PFS) but not overall survival (OS). Its use in LAPC may improve local control (LC) and delay systemic spread. GFG is a study of induction (ind) Gem-Ox, then 5FU-3DRT, then consolidation (con) Gem-Ox. Primary outcome is feasibility using proportion of patients (pts) receiving > 80% planned dose for each component. Secondary outcomes are safety, activity and QOL. Methods: Pts with previously untreated inoperable LAPC, M0, measurable disease, ECOG 0–2 were given Gem (1000mg/m2 d1 + d15 q28), Ox (100mg/m2 d2 + d16 q28) in both ind (1 cycle) & con (3 cycles), & 5FU 200mg/m2/d over 6 weeks during RT of 54Gy in 30 fractions of 1.8Gy. Results: 48 pts were enrolled, median age 61y (44–81y), PS 0/1=96%, regional lymph nodes=44%, T4=46%. Worst grade (G) for anaemia (10%); fatigue, nausea (8%); diarrhoea, vomiting, neutropenia, infection (4%); stomatitis, anorexia (2%) was G3. Thrombocytopenia was G3=2% G4=2%; liver function was G3=23% G4=6%; late radiation toxicity was G3=2% G4=2% (both gastric bleeding). Half of all pts completed all planned cycles (24 pts); 29% of pts received >80% of all treatment (14 pts); 70% of pts received >80% of all chemoradiation (33 pts). Pts ceased treatment for toxicity (16%), PD (21%) or doctor/pt preference (4/2%). Global QOL did not significantly change from baseline. Median duration of LC, PFS, OS were 15.8, 9.9, 15.4m at median follow up of 29.7m. Exploratory analysis of age, disease stage, PS, CA19–9 or WCC found no univariate predictors of PFS or treatment completion. 8/48 pts survived >24m. Conclusions: Compared to our previous study using the same radiation schedule, addition of oxaliplatin was associated with improved LC, PFS & OS (prev. 11.9, 7.1 & 11.7m) without significant offset by toxicity. The extended duration of LC and a subset who had a very prolonged benefit may be due to patient selection but equally may suggest an incremental benefit from more intensive systemic therapy requiring further study in controlled trials. [Table: see text]

Within the past year significant advances in the development of high-performance vertical-cavity surface-emitting laser (VCSELs) and quantum-well modulators has been achieved. Large arrays of VCSELs with submilliamp thresholds and diffraction limited beams have been produced by MBE growth of InGaAs/GaAs strained-layer quantum-well active regions encompassed by integral AlAs/GaAs quarter-wave stack mirrors. Also, using similar technology, asymmetric transverse Fabry-Perot modulators with transfer efficiencies about 20 percent/V and high-extinction on/off modulation with voltage swing of only 2 volts have been demonstrated. Using superlattice active regions, room-temperature blue shifted absorption modulators have been produced, and self-electrooptic effect devices with record on/off ratios (more than 100:1) have been achieved.

1516 Background: The International Breast Cancer Intervention Study (IBIS-1) found that 5 years of TAM compared to placebo reduced the incidence of invasive breast cancer in women at increased risk...

20557 Background: Trastuzumab induced cardiotoxicity may warrant discontinuation of therapy in up to 19% of women with early stage breast cancer, and is measured through assessment of left ventricular ejection fraction (LVEF). Previous studies have shown that elevated serum troponin I levels (Trop I - a cardiomyocyte structural protein) predict anthracycline-induced cardiac dysfunction prior to a decrease in LVEF. N-terminal pro-B type natriuretic peptide (NT pro-BNP) is a marker of increased left ventricular wall tension that may detect trastuzumab-induced heart dysfunction. Methods: We performed a cross sectional study in women receiving trastuzumab for breast cancer. Patients were required to have a normal LVEF and no clinical signs of heart failure. Serum Trop I and NT pro-BNP were assayed immediately prior to trastuzumab infusion (t0; n=36) and 24 hours later (t24; n=31). Results: Patient characteristics were: mean age 52 (range 25–86); 30 (83%) anthracycline pre-treated; 23 (64%) early stage and 13 ...

We present a technique, quality adjusted survival analysis, for the analysis of controlled trials where patients may experience several health states which differ in their quality of life. When the data are censored, a survival analysis of the quality adjusted life years achieved may involve informative censoring, and produce biased estimates. To overcome this, we partition the survival curve; the resulting areas, which represent the mean time in each state, are multiplied by utility weights to provide an unbiased estimate of (restricted) quality adjusted survival. If the appropriate weights are in doubt, the results are best presented as a threshold analysis over the utility weights, allowing individual recommendation to be read from a simple graph. The certainty of the conclusions can be presented as confidence bands on the threshold line. The techniques are illustrated with a re-analysis of a large three-arm trial of adjuvant chemoendocrine therapy for stage II breast cancer in postmenopausal women. This shows that if the value of time spent in toxicity is greater than the time spent in relapse, we can be 95 per cent confident that chemoendocrine therapy is the preferred option.

Currently, there exists an intensive research effort for practical optical modulators in III–V semiconductors for potential uses in optical interconnections of integrated circuits and information processing.1 One of the important considerations is low drive power, e.g., low operating voltage swing in electro-optical modulators. Waveguide devices tend to provide low drive voltages (~1 V) because the field is applied perpendicular to the light propagation direction; however, the coupling of the light into the waveguide adds complexity to practical implementations. On the other hand, although coupling is relatively easy, surface-normal devices tend to require high drive voltages ( > 10 V) because of short interaction lengths. Another important device parameter is the amount of input power that is modulated into the output power. Using a figure-of-merit, normalized electro-optic transfer function (M v ), defined as the percentage modulation of the input light per unit driven voltage to relate the transfer function of electro-optic modulators between the electrical and optical signals, previous transverse modulators have M v values of ~8%/V, and efficient waveguide modulators have a representative value of ≤ 15%/V.1 Here we report a normally-on electroabsorptive surface-normal Fabry–Perot (FP) reflection modulator with an ~80% top mirror and an active region of 24 quantum wells to achieve a reflection change of >45% for an operating voltage swing of only ~ V, with a contrast ratio of more than 15. The wavelength range over which more than half this reflection change is observed extends as wide as 7 nm. Such devices compete effectively with low-voltage waveguide modulators, with further advantages of easy coupling and compact sizes, i.e., small capacitances.

6528 Background: Small benefits are judged sufficient to make ACT worthwhile by women who have had either 6 cycles of CMF or 4 cycles of AC. We sought to determine the benefits needed to make longer and more intensive regimens worthwhile. Methods: 293 women who completed ACT 3 to 39 months earlier were presented 4 hypothetical scenarios based on known survival times (5 and 15 years) and rates (65% and 85% at 5 years) without ACT using validated, standardised interviews. 179 were in a randomized trial (BIG 02–98) testing addition of docetaxel (T) to a standard regimen including doxorubicin (A) and classical CMF; 114 were treated outside of the trial at the same centres. Women also rated their recollections of health-related quality of life during ACT. Results: The median age was 55 (range 25 to 78), 36% had a college or university degree, and 62% had dependants. The regimens (and their duration) in the trial were: 4 cycles of A or AC then 3 cycles of CMF (24w) in 31% of the women; 4 cycles of AT followed by 4 cycles of CMF (24w) in 29%; and 3 cycles of A then 3 cycles of T then 3 cycles of CMF (30w) in 40%. The regimens outside of the trial were: 4 cycles of AC (12w) in 52%; 6 cycles of CMF (24w) in 20%; and 4 cycles of AC then 3 cycles of CMF (24w) in 23%. A 2% gain in 5-year survival rates or a 6-month gain in survival duration was judged sufficient to make ACT worthwhile by 62–67% of women. Gains of more than 5% in 5-year survival rates or more than 2 years in survival duration were judged necessary to make ACT worthwhile by 10–20% of women. Women's preferences were strongly associated with the aversiveness of their treatment. Women who had more problems with physical well-being, coping with treatment, and nausea or vomiting judged larger benefits necessary to make their ACT worthwhile (p.2). Conclusions: As in previous studies, small benefits were judged sufficient to make ACT worthwhile, even if it lasted 6–7 months, and included docetaxel, doxorubicin and CMF. No significant financial relationships to disclose.

6500 Background: Treatments for cancer have a myriad of beneficial and harmful effects. Benefits include prolonging survival and relieving cancer symptoms. Harms include side effects, inconvenience and costs. Assessing the overall impact of treatments requires a single, precise measure of net benefit, which combines information about health-related QoL, disease control and survival. Our aim is to develop a system for converting data from a QoL questionnaire into valid utilities, which allows comparison of treatments tested in clinical trials using utility measures and quality-adjusted survival analysis. Methods: 200 cancer patients previously completed the Utility-Based Questionnaire-Cancer (UBQ-C), a validated cancer-specific QoL measure which includes scales of health status (1 item), overall QoL (1 item), disabilities (12 items) and distresses (20 items); and were interviewed to elicit utilities using time trade-off (TTO) techniques. Scores were standardized to a scale bounded by 0 (worst outcome or death) and 1 (best possible health). A global QoL measure was derived from a weighted combination of the UBQ-C scales. Linear regression of overall health status on scales determined the weights. An equation to convert global QoL into utility was derived. Results: The global QoL measure as derived from the UBQ-C scales was more precise than the single- item scales. Median scores (IQR) were much lower for the global QoL measure: 0.77 (0.65–0.85) than for the direct measure of utility: TTO 0.98 (0.85 to 1.0). The best model to predict utility from derived global QoL was a power transformation: TTO=1-(1-global QoL)2.1. The mean absolute error in predicting utilities was 0.02. Conclusions: QoL measures underestimate utilities. A global QoL measure based on a weighted combination of the single item scales is more precise than single-item QoL scales. Our work enables QoL data obtained with a simple questionnaire to be converted into valid utilities that can be used in clinical trials to (i) describe the effects of cancer treatments on QoL (accounting for trade-offs between disparate aspects), (ii) evaluate trade-offs between quality and quantity of life, and (iii) do cost- effectiveness analysis. No significant financial relationships to disclose.

9002 Background: Depression, anxiety, fatigue and impaired well-being are common, important and closely related in advanced cancer. We sought to determine the effects of sertraline (a well-tolerated, SSRI antidepressant) on these symptoms and survival in a broad cross-section of people with advanced cancer but without major depression. Methods: 189 participants (pts) were randomly allocated to sertraline 50 mg daily or placebo. Assessments were at baseline; months 1, 2, 4, 6, 9, 12; and, then 3-monthly. Outcome measures rated by pts included the: Centre for Epidemiologic Studies Depression scale (CES-D); Hospital Anxiety and Depression Scale (HADS-A, HADS-D); and the Functional Assessment of Cancer Therapy General and Fatigue scales (FACT-G and FACT-F). Clinicians completed Spitzer's Quality of Life Index (SQLI). Outcomes on all scales are expressed from 0 (worst) to 100 (best). The primary analyses of sertraline's effects on quality of life were based on scores at 4 and 8 weeks adjusted for baseline scores using generalised estimating equations. Efficacy analyses are by intention to treat; toxicity analyses by treatment received. P-values and 95% confidence intervals (CI) are 2-sided. Results: Recruitment was stopped after the first planned interim analysis of 150 pts showed a trend in overall survival favouring placebo (univariable logrank p=0.04; multivariable Cox model hazard ratio 1.61, CI 1.1 to 2.5, p=0.02). This trend was weaker at the final analysis including all 189 patients and longer follow-up (univariable logrank p=0.09); and, after accounting for baseline factors (multivariable Cox model hazard ratio 1.27, CI 0.87 to 1.8, p=0.2). Sertraline had no significant effects (scale: benefit over placebo, 95% CI) on depression (CES-D: 0.4, −2.6 to 3.4), anxiety (HADS-A: 2.0, −1.5 to 5.5), fatigue (FACT-F: 0.3, −4.3 to 4.9), overall quality of life (FACT-G: 1.7, −1.3 to 4.7) or clinicians’ ratings (SQLI: 2.0, −2.5 to 6.5). Subgroup and sensitivity analyses also excluded significant benefits. Sertraline was discontinued more often and earlier than placebo (logrank p = 0.03). The trial was closed for lack of benefit. Conclusions: Sertraline did not improve symptoms, well-being or survival and should be reserved for those with a proven indication. No significant financial relationships to disclose.

Purpose We sought to determine which outcome measures were most sensitive at detecting the benefits of Sentinel node based management (SNBM) over routine axillary clearance (RAC) in the SNAC trial. Patients and Methods 1088 women with early breast cancer were randomised to either SNBM or RAC. The primary endpoint was the percent increase in arm volume based on clinicians’ measurements of arm circumference at 10cm intervals. Secondary endpoints included patients self-ratings of arm swelling and other aspects of quality of life, assessed using the SNAC Study Specific Scales (SSSS: 15 questions asking about symptoms, dysfunction and disabilities). We report a comparison of the relative sensitivity of these endpoints in detecting differences between the treatment groups. Results Patients’ ratings on the SSSS were 3.2 times as sensitive as clinicians’ ratings of arm swelling, requiring 68% fewer patients to detect a given treatment effect. The 7 questions asking patients about symptoms were most sensitive. Questions asking about dysfunctions and disabilities were less sensitive. Conclusion Patient-rated measures were more sensitive in this trial than clinician-rated measures at distinguishing the effects of SNBM and RAC. Similar trials would require only a third as many patients if the primary endpoint was rated by patients rather than clinicians.

6074 Background: Cancer patients are encouraged to include their partners in making decisions about treatment. We compared the preferences of women who had ACT for EBC with those of their partners....

787 Background: ACT for EBC improves survival but is inconvenient and has side effects. Past studies of preferences show that many women who have had ACT for EBC consider small benefits sufficient to make it worthwhile (Lancet Oncol 2001; 2: 691). We sought predictors of these preferences. Methods: 118 consecutive consenting women who completed ACT 3 to 34 months previously (mean 18) were presented 4 hypothetical scenarios based on known survival times (5 and 15 yrs) and rates (65% and 85% at 5 yrs) with and without ACT. All women provided data on demographics, disease, treatment and side effects of ACT. A representative subset of 83 women also completed validated scales assessing anxiety, depression, optimism, perceived cause and impact of breast cancer. Associations were assessed with linear regression after normal score transformation of preferences. Results: Median age was 55 (range 24 to 69), 68% had a current partner, 45% had tertiary education, 68% were employed, 79% had children, 54% had dependant...

6113 Background: Treatment with high dose cisplatin (HDC) previously required an inpatient (IP) admission with an overnight stay in hospital. Improvements in supportive care mean HDC can now be given as an out-patient (OP) regimen without an overnight stay in hospital. The aim of this trial was to determine whether it is preferable to give HDC as an IP or OP regimen. Methods: Eligible patients were starting CT with 2 or more cycles or HDC (100mg or more per dose) and were suitable for treatment as an OP (adequate transport, support, telephone, no significant comorbidities). All were to have an IP cycle and an OP cycle; the order (IP or OP first) was randomly allocated. Prehydration, antiemetics and administration of HDC were identical for IP and OP. IP went home the next morning after 3L of NS over 18 hrs. OP went home the same day after 2L NS over 6 hrs, and were phoned the next morning. The primary outcome was whether patients preferred treatment as an IP or OP. Secondary outcomes included aspects of he...