Summary Background The role of adjuvant bisphosphonates in early breast cancer is uncertain. We therefore did a large randomised trial to investigate the effect of the adjuvant use of zoledronic acid ...on disease-free survival (DFS) in high-risk patients with early breast cancer. Methods In the AZURE trial, an open-label, international, multicentre, randomised, controlled, parallel-group phase 3 trial, women (age ≥18 years) with stage II or III breast cancer were randomly assigned (1:1) by a central automated 24-h computer-generated telephone minimisation system (balanced for number of involved axillary lymph nodes, tumour stage, oestrogen receptor status, type and timing of systemic therapy, menopausal status, statin use, and treatment centre) to receive standard adjuvant systemic treatment alone (control group) or with 4 mg intravenous zoledronic acid every 3–4 weeks for six doses, then every 3 months for eight doses, followed by every 6 months for five doses, for a total of 5 years of treatment. The primary endpoint was disease-free survival (DFS). Secondary endpoints were invasive DFS (IDFS), overall survival, time to bone metastases, time to distant recurrence, and subgroup analyses of variables included in the randomisation. All patients have completed study treatment. Results from the intention-to-treat final analysis of this fully recruited study are presented after a median follow-up of 84 months (IQR 66–93). This final efficacy analysis was planned to take place after 940 DFS events. This trial is registered with ClinicalTrials.gov , NCT00072020. Findings 3360 women were recruited from 174 centres in seven countries between Sept 4, 2003, and Feb 16, 2006. The number of DFS events did not differ between groups: 493 in the control group and 473 in the zoledronic acid group (adjusted hazard ratio HR 0·94, 95% CI 0·82–1·06; p=0·30). IDFS (HR 0·93, 95% CI 0·82–1·05; p=0·22), overall survival (0·93, 0·81–1·08; p=0·37), and distant recurrences (0·93, 0·81–1·07; p=0·29) were much the same in both groups. Zoledronic acid reduced the development of bone metastases, both as a first event (HR 0·78, 95% CI 0·63–0·96; p=0·020) and at any time during follow-up (0·81, 0·68–0·97; p=0·022). The effects of zoledronic acid on DFS were not affected by oestrogen-receptor status. However, zoledronic acid improved IDFS in those who were over 5 years since menopause at trial entry (n=1041; HR 0·77, 95% CI 0·63–0·96) but not in all other (premenopause, perimenopause, and unknown status) menopausal groups (n=2318; HR 1·03, 95% CI 0·89–1·20). 33 cases of suspected osteonecrosis of the jaw have been reported, with 26 confirmed on central review, all in the zoledronic acid group (1·7%, 95% CI 1·0–2·4). Interpretation These results suggest no overall benefit from the addition of zoledronic acid to standard adjuvant treatments for early breast cancer. However, zoledronic acid does reduce the development of bone metastases and, for women with established menopause, improved disease outcomes. Funding Novartis Global and NIHR Cancer Research Network.
Summary Background Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is ...derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer. Methods In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m2 intravenous irinotecan every 3 weeks (300 mg/m2 if aged ≥70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146 , BRAF, NRAS , and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876. Results Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12–13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1·01, 95% CI 0·83–1·23; p=0·91), but individuals in the IrPan group had longer progression-free survival (0·78, 0·64–0·95; p=0·015) and a greater number of responses (79 34% patients vs 27 12%; p<0·0001) than did individuals in the irinotecan group. Grade 3 or worse diarrhoea (64 29% of 219 patients vs 39 18% of 218 patients), skin toxicity (41 19% vs none), lethargy (45 21% vs 24 11%), infection (42 19% vs 22 10%) and haematological toxicity (48 22% vs 27 12%) were reported more commonly in the IrPan group than in the irinotecan group. We recorded five treatment-related deaths, two in the IrPan group and three in the irinotecan group. Interpretation Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours. Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents. Funding Cancer Research UK, Amgen Inc.
Objectives To review the literature on pharmacological treatments for fibromyalgia. Methods Relative efficacy was estimated in terms of outcome measures highlighted by the Outcome Measures in ...Rheumatology Network using a Bayesian mixed treatment comparison (MTC) meta-analysis. Randomized controlled trials reporting treatments for fibromyalgia were identified by systematically reviewing electronic databases (Cochrane Library, Medline, EMBASE; accessed February 2008) and conducting manual bibliographic searches. Results Forty-five randomized controlled trials met the prespecified inclusion criteria for the systematic review. There were limited robust clinical data for some therapeutic classes (tricyclic antidepressants, analgesics, sedative hypnotics, monoamine oxidase inhibitors) and only 21 studies met the more stringent criteria for inclusion in the MTC. The majority of studies included in the MTC assessed the anticonvulsant pregabalin ( n = 5) or the serotonin norepinephrine reuptake inhibitors (SNRIs) duloxetine ( n = 3) and milnacipran ( n = 3). Licensed doses of pregabalin and duloxetine were significantly ( P < 0.05) more efficacious than placebo in terms of absolute reduction in pain, number of “responders” (≥30% reduction in pain), or change in Fibromyalgia Impact Questionnaire score (pregabalin 450 mg/d only). There was no significant difference between licensed doses of pregabalin and duloxetine for these outcomes. However licensed doses of pregabalin produced significantly greater improvements in sleep compared with milnacipran (as measured by Medical Outcomes Study Sleep Scale). Conclusions The current study confirms the therapeutic efficacy of pregabalin and the SNRIs, duloxetine and milnacipran, in the treatment of fibromyalgia. Given their different modes of action, combination therapy with pregabalin plus an SNRI should be investigated in future research.
Summary Background The CRIMSON (CRisis plan IMpact: Subjective and Objective coercion and eNgagement) study is an individual level, randomised controlled trial that compared the effectiveness of ...Joint Crisis Plans (JCPs) with treatment as usual for people with severe mental illness. The JCP is a negotiated statement by a patient of treatment preferences for any future psychiatric emergency, when he or she might be unable to express clear views. We assessed whether the additional use of JCPs improved patient outcomes compared with treatment as usual. Methods Patients were eligible if they had at least one psychiatric admission in the previous 2 years and were on the Enhanced Care Programme Approach register. The study was done with 64 generic and specialist community mental health teams in four English mental health care provider organisations (trusts). Hypotheses tested were that, compared with the control group, the intervention group would experience: fewer compulsory admissions (primary outcome); fewer psychiatric admissions; shorter psychiatric stays; lower perceived coercion; improved therapeutic relationships; and improved engagement. We stratified participants by centre. The research team but not participants nor clinical staff were masked to allocation. This study is registered with ClinicalTrials.gov , number ISRCTN11501328. Findings 569 participants were randomly assigned (285 to the intervention group and 284 to the control group). No significant treatment effect was seen for the primary outcome (56 20% sectioned in the control group and 49 18% in the JCP group; odds ratio 0·90 95% CI 0·58–1·39, p=0·63) or any secondary outcomes, with the exception of an improved secondary outcome of therapeutic relationships (17·3 7·6 vs 16·0 7·1; adjusted difference −1·28 95% CI −2·56 to −0·01, p=0·049). Qualitative data supported this finding. Interpretation Our findings are inconsistent with two earlier JCP studies, and show that the JCP is not significantly more effective than treatment as usual. There is evidence to suggest the JCPs were not fully implemented in all study sites, and were combined with routine clinical review meetings which did not actively incorporate patients' preferences. The study therefore raises important questions about implementing new interventions in routine clinical practice. Funding Medical Research Council UK and the National Institute for Health Research.
This study compared community response prior to and during the H1N1 2009 influenza pandemic using a cross-sectional phone survey of rural and metropolitan South Australia, conducted in 2007 and 2009. ...Awareness of pandemic influenza was significantly higher and anxiety lower in 2009 than in 2007. Reported seasonal influenza vaccine uptake increased from 51.7% in 2007 to 61.4% in 2009, but there was more interest in receiving pandemic vaccine in 2007 (87.5%) than in 2009 (57%).
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