Quality-adjusted survival as an end point in breast cancer trials

Breast cancer treatment recommendations will often require an appraisal of likely benefits in relation to likely side-effects on survival and quality of life (QoL) endpoints, and possibly also an evaluation of the size of the anticipated net clinical benefit against financial costs. Quality-adjusted survival (QAS) analysis methods provide a formal approach for deriving an estimate of net clinical benefit to facilitate this appraisal process. QAS analysis methods have been applied in trials with breast cancer patients of adjuvant therapies as well as treatments for advanced/metastatic disease. QAS analyses based solely on trial data may fail to capture plausible longer-term benefits; thus methods to explore the possible outcomes of treatment beyond the limits of trial data have been developed. These modelling approaches can help researchers gain insights and identify future research priorities, but do not replace the need for long-term evidence from randomised trials.NHMR

Which lipid measurement should we monitor? An analysis of the LIPID study

OBJECTIVES: To evaluate the optimal lipid to measure in monitoring patients, we assessed three factors that influence the choice of monitoring tests: (1) clinical validity; (2) responsiveness to therapy changes and (3) the size of the long-term ‘signal-to-noise’ ratio. DESIGN: Longitudinal analyses of repeated lipid measurement over 5 years. SETTING: Subsidiary analysis of a Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study—a clinical trial in Australia, New Zealand and Finland. PARTICIPANTS: 9014 patients aged 31–75 years with previous acute coronary syndromes. INTERVENTIONS: Patients were randomly assigned to 40 mg daily pravastatin or placebo. PRIMARY AND SECONDARY OUTCOME MEASURES: We used data on serial lipid measurements—at randomisation, 6 months and 12 months, and then annually to 5 years—of total cholesterol; low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and their ratios; triglycerides; and apolipoproteins A and B and their ratio and their ability to predict coronary events. RESULTS: All the lipid measures were statistically significantly associated with future coronary events, but the associations between each of the three ratio measures (total or LDL cholesterol to HDL cholesterol, and apolipoprotein B to apolipoprotein A1) and the time to a coronary event were better than those for any of the single lipid measures. The two cholesterol ratios also ranked highly for the long-term signal-to-noise ratios. However, LDL cholesterol and non-HDL cholesterol showed the most responsiveness to treatment change. CONCLUSIONS: Lipid monitoring is increasingly common, but current guidelines vary. No single measure was best on all three criteria. Total cholesterol did not rank highly on any single criterion. However, measurements based on cholesterol subfractions—non-HDL cholesterol (total cholesterol minus HDL cholesterol) and the two ratios—appeared superior to total cholesterol or any of the apolipoprotein options. Guidelines should consider using non-HDL cholesterol or a ratio measure for initial treatment decisions and subsequent monitoring

Linking the evidence: intermediate outcomes in medical test assessments

Objectives To review how health technology assessments (HTA) of medical tests incorporate intermediate outcomes in conclusions about the effectiveness of tests on improving health outcomes. Methods Systematic review of English-language test assessments in the HTA database from January 2005 to February 2010, supplemented by a search of the websites of International Network of Agencies for Health Technology Assessment (INAHTA) members. Results 149 HTAs from eight countries were assessed. Half evaluated tests for screening or diagnosis, a third for disease classification (including staging, prognosis, monitoring), and a fifth for multiple purposes. In 71 HTAs (48%) only diagnostic accuracy was reported, while in 17 (11%) evidence of health outcomes was reported in addition to accuracy. Intermediate outcomes, mainly the impact of test results on patient management, were considered in 61 HTAs (41%). Of these, 47 identified randomized trials or observational studies reporting intermediate outcomes. The validity of these intermediate outcomes as a surrogate for health outcomes was not consistently discussed; nor was the quality appraisal of this evidence. Clear conclusions about whether the test was effective were included in about 60% of HTAs. Conclusions Intermediate outcomes are frequently assessed in medical test HTAs, but interpretation of this evidence is inconsistently reported. We recommend that reviewers explain the rationale for using intermediate outcomes, identify the assumptions required to link intermediate outcomes and patient benefits and harms, and assess the quality of included studies

Low-dose aspirin for preventing recurrent venous thromboembolism

Patients who have had a first episode of unprovoked venous thromboembolism have a high risk of recurrence after anticoagulants are discontinued. Aspirin may be effective in preventing a recurrence of venous thromboembolism. Methods We randomly assigned 822 patients who had completed initial anticoagulant therapy after a first episode of unprovoked venous thromboembolism to receive aspirin, at a dose of 100 mg daily, or placebo for up to 4 years. The primary outcome was a recurrence of venous thromboembolism. Results During a median follow-up period of 37.2 months, venous thromboembolism recurred in 73 of 411 patients assigned to placebo and in 57 of 411 assigned to aspirin (a rate of 6.5% per year vs. 4.8% per year; hazard ratio with aspirin, 0.74; 95% confidence interval [CI], 0.52 to 1.05; P = 0.09). Aspirin reduced the rate of the two prespecified secondary composite outcomes: the rate of venous thromboembolism, myocardial infarction, stroke, or cardiovascular death was reduced by 34% (a rate of 8.0% per year with placebo vs. 5.2% per year with aspirin; hazard ratio with aspirin, 0.66; 95% CI, 0.48 to 0.92; P = 0.01), and the rate of venous thromboembolism, myocardial infarction, stroke, major bleeding, or death from any cause was reduced by 33% (hazard ratio, 0.67; 95% CI, 0.49 to 0.91; P = 0.01). There was no significant between-group difference in the rates of major or clinically relevant nonmajor bleeding episodes (rate of 0.6% per year with placebo vs. 1.1% per year with aspirin, P = 0.22) or serious adverse events. Conclusions In this study, aspirin, as compared with placebo, did not significantly reduce the rate of recurrence of venous thromboembolism but resulted in a significant reduction in the rate of major vascular events, with improved net clinical benefit. These results substantiate earlier evidence of a therapeutic benefit of aspirin when it is given to patients after initial anticoagulant therapy for a first episode of unprovoked venous thromboembolism. (Funded by National Health and Medical Research Council [Australia] and others; Australian New Zealand Clinical Trials Registry number, ACTRN12605000004662.)Health Research Council (New Zealand), Australasian Society of Thrombosis and Hemostasis, National Heart Foundation of Australia, Bayer HealthCare, National Health and Medical Research Council (Australia) program grant 103778

A Systematic Review of Physicians' Survival Predictions in Terminally Ill Cancer Patients

Objective: To systematically review the accuracy of physicians’ clinical predictions of survival in terminally ill cancer patients. Data sources: Cochrane Library, Medline (1996-2000), Embase, Current Contents, and Cancerlit databases as well as hand searching. Study selection: Studies were included if a physician’s temporal clinical prediction of survival (CPS) and the actual survival (AS) for terminally ill cancer patients were available for statistical analysis. Study quality was assessed by using a critical appraisal tool produced by the local health authority. Data synthesis: Raw data were pooled and analysed with regression and other multivariate techniques. Results: 17 published studies were identified; 12 met the inclusion criteria, and 8 were evaluable, providing 1563 individual prediction-survival dyads. CPS was generally overoptimistic (median CPS 42 days, median AS 29 days); it was correct to within one week in 25% of cases and overestimated survival by at least four weeks in 27%. The longer the CPS the greater the variability in AS. Although agreement between CPS and AS was poor (weighted k 0.36), the two were highly significantly associated after log transformation (Spearman rank correlation 0.60, P < 0.001). Consideration of performance status, symptoms, and use of steroids improved the accuracy of the CPS, although the additional value was small. Heterogeneity of the studies’ results precluded a comprehensive meta-analysis. Conclusions: Although clinicians consistently overestimate survival, their predictions are highly correlated with actual survival; the predictions have discriminatory ability even if they are miscalibrated. Clinicians caring for patients with terminal cancer need to be aware of their tendency to overestimate survival, as it may affect patients’ prospects for achieving a good death. Accurate prognostication models incorporating clinical prediction of survival are needed.Sociolog

The cost effectiveness of bevacizumab when added to capecitabine, with or without mitomycin-C, in first line treatment of metastatic colorectal cancer: results from the Australasian phase III MAX study

Background: Based on the clinical data, bevacizumab has been approved in Australia and globally for the treatment of advanced colorectal cancer. However, limited evidence exists for its cost-effectiveness. The purpose of this study was to evaluate the cost effectiveness of adding bevacizumab to capecitabine monotherapy in patients with metastatic colorectal cancer, using data from the prospective economic evaluation conducted alongside the MAX trial. Methods: Individual patient level data on resource use and progression free survival were prospectively collected in the phase III MAX trial. Resource use data were collected for the period between randomisation and disease progression, and unit costs were assigned from the perspective of the Australian health care funder. Effectiveness was measured in quality adjusted progression free survival years, with utility scores obtained from both the community valued EQ-5D questionnaire and the patient valued UBQ-C questionnaire. Progression free survival was used as a secondary effectiveness measure. Results: The addition of bevacizumab to capecitabine monotherapy cost approximately $192,156 (95$135,619 to $326,894) per quality adjusted progression free survival year gained when using publicly listed pharmaceutical prices and utility values from the EQ-5D questionnaire. This decreased to$149,455 (95% CI, $100,356 to$245,910) when values from the UBQ-C questionnaire were applied. The incremental cost per progression free survival year was $145,059 (95$106,703 to $233,225). Conclusions: Bevacizumab was not found to be cost effective at its listed price, based on results from the MAX trial.Roche Products Pty Lt

The cost effectiveness of bevacizumab when added to capecitabine, with or without mitomycin-C, in first line treatment of metastatic colorectal cancer: results from the Australasian phase III MAX study

Background: Based on the clinical data, bevacizumab has been approved in Australia and globally for the treatment of advanced colorectal cancer. However, limited evidence exists for its cost-effectiveness. The purpose of this study was to evaluate the cost effectiveness of adding bevacizumab to capecitabine monotherapy in patients with metastatic colorectal cancer, using data from the prospective economic evaluation conducted alongside the MAX trial. Methods: Individual patient level data on resource use and progression free survival were prospectively collected in the phase III MAX trial. Resource use data were collected for the period between randomisation and disease progression, and unit costs were assigned from the perspective of the Australian health care funder. Effectiveness was measured in quality adjusted progression free survival years, with utility scores obtained from both the community valued EQ-5D questionnaire and the patient valued UBQ-C questionnaire. Progression free survival was used as a secondary effectiveness measure. Results: The addition of bevacizumab to capecitabine monotherapy cost approximately $192,156 (95$135,619 to $326,894) per quality adjusted progression free survival year gained when using publicly listed pharmaceutical prices and utility values from the EQ-5D questionnaire. This decreased to$149,455 (95% CI, $100,356 to$245,910) when values from the UBQ-C questionnaire were applied. The incremental cost per progression free survival year was $145,059 (95$106,703 to $233,225). Conclusions: Bevacizumab was not found to be cost effective at its listed price, based on results from the MAX trial.Roche Products Pty Lt

Progression-free survival as a surrogate endpoint for overall survival in modern ovarian cancer trials: A meta-analysis

Background: Progression-free survival (PFS) has been adopted as the primary endpoint in many randomized controlled trials, and can be determined much earlier than overall survival (OS). We investigated whether PFS is a good surrogate endpoint for OS in trials of first-line treatment for epithelial ovarian cancer (EOC), and whether this relationship has changed with the introduction of new treatment types. Methods: In a meta-analysis, we identified summary data [hazard ratio (HR) and median time] from published randomized controlled trials. Linear regression was used to assess the association between treatment effects on PFS and OS overall, and for subgroups defined by treatment type, postprogression survival (PPS) and established prognostic factors. Results: Correlation between HRs for PFS and OS, in 26 trials with 30 treatment comparisons comprising 24,870 patients, was modest (r2 = 0.52, weighted by trial sample size). The correlation diminished with recency: preplatinum/paclitaxel era, r2 = 0.66; platinum/paclitaxel, r2 = 0.44; triplet combinations, r2 = 0.22; biologicals, r2 = 0.30. The median PPS increased over time for the experimental (Ptrend = 0.03) and control arms (Ptrend = 0.003). The difference in median PPS between treatment arms strongly correlated with the difference in median OS (r2 = 0.83). In trials where the control therapy had median PPS of less than 18 months, correlation between PFS and OS was stronger (r2 = 0.64) than where the median PPS was longer (r2 = 0.48). Conclusions: In EOC, correlation in the relative treatment effect between PFS and OS in first-line platinum-based chemotherapy randomized controlled trials is moderate and has weakened with increasing availability of effective salvage therapies

Sentinel-lymph-node-based management or routine axillary clearance? Three-year outcomes of the RACS Sentinel Node Biopsy versus Axillary Clearance (SNAC) 1 trial

Purpose We sought to determine whether the benefits of sentinel-node-based management (SNBM) over routine axillary clearance (RAC) at 1 year persisted to 3 years of follow-up. Methods 1088 women with clinically node negative breast cancer were randomly assigned to SNBM versus RAC. Upper limb volume, symptoms and function were assessed at 1, 6, 12, 24 and 36 months after surgery objectively with upper limb measurements by clinicians, and subjectively by patients’ using validated self-rating scales. Results Upper limb volume increased in both groups over the first 2 years and differed between the two groups all time points beyond 1 month (P<0.02), but then plateaued. Upper limb swelling was no worse in women who had axillary clearance as two-stage procedure than in women assigned RAC as a one-stage procedure. Upper limb volume had increased 15% or more in 6.0% at 6 months and 17.6% at 3 years in those assigned RAC versus 4.2% and 11.9% in those assigned SNBM. Reductions in upper limb movement were also greater with RAC than SNBM over 6 months, but improved and were similar in the two groups from 1 to 3 years. Subjective ratings of upper limb swelling, symptoms, dysfunction, and disability over 3 years were worse in the RAC group. Upper limb swelling at 3 years was rated severe by few women (1.1%), but moderate by 9.4% in the RAC group and 2.5% in the SNBM group (P<0.001). Conclusions The benefits of SNBM over RAC persist 3 years after surgery.Royal Australasian College of Surgeon