288 research outputs found
Cetuximab therapy in first-line metastatic colorectal cancer and intermittent palliative chemotherapy: review of the COIN trial.
No full textThe aim of palliative chemotherapy is to increase survival whilst maintaining maximum quality of life for the individual concerned. It is evident that the survival advantage offered by palliative chemotherapy for metastatic colorectal cancer has increased incrementally with the addition of each newly licensed therapeutic agent. More recently, advances in the field have led to the introduction of targeted monoclonal antibodies, whose benefits are documented in clinical trials and are acknowledged in their approval and licensing. Whilst we are continuing to explore the optimum use of the more traditional chemotherapy agents, with respect to both quantity and quality of life, these novel agents are battling to find their optimum place in the armamentarium. It is evident that a continuing add-one-in policy is likely to be detrimental to both patient and budget. Defining the positioning and duration of these combination therapies has become the subject of much debate and numerous current clinical trials. The Medical Research Council COIN trial is one of these trials, with a remit to explore further the optimum use of both standard agents and novel agents in the first-line setting for metastatic colorectal cancer
FRAGMATIC: A randomised phase III clinical trial investigating the effect of <b>fragm</b>in<sup>® </sup><b>a</b>dded to standard <b>t</b>herapy <b>i</b>n patients with lung <b>c</b>ancer
No full textAbstract Background Venous thromboembolism (VTE) occurs when blood clots in the leg, pelvic or other deep vein (deep vein thrombosis) with or without transport of the thrombus into the pulmonary arterial circulation (pulmonary embolus). VTE is common in patients with cancer and is increased by surgery, chemotherapy, radiotherapy and disease progression. Low molecular weight heparin (LMWH) is routinely used to treat VTE and some evidence suggests that LMWH may also have an anticancer effect, by reduction in the incidence of metastases. The FRAGMATIC trial will assess the effect of adding dalteparin (FRAGMIN), a type of LMWH, to standard treatment for patients with lung cancer. Methods/Design The study design is a randomised multicentre phase III trial comparing standard treatment and standard treatment plus daily LMWH for 24 weeks in patients with lung cancer. Patients eligible for this study must have histopathological or cytological diagnosis of primary bronchial carcinoma (small cell or non-small cell) within 6 weeks of randomisation, be 18 or older, and must be willing and able to self-administer 5000 IU dalteparin by daily subcutaneous injection or have it administered to themselves or by a carer for 24 weeks. A total of 2200 patients will be recruited from all over the UK over a 3 year period and followed up for a minimum of 1 year after randomisation. Patients will be randomised to one of the two treatment groups in a 1:1 ratio, standard treatment or standard treatment plus dalteparin. The primary outcome measure of the trial is overall survival. The secondary outcome measures include venous thrombotic event (VTE) free survival, serious adverse events (SAEs), metastasis-free survival, toxicity, quality of life (QoL), levels of breathlessness, anxiety and depression, cost effectiveness and cost utility. Trial registration Current Controlled Trials ISRCTN80812769</p
BA08: An open-label, single-arm, non-randomised, phase 2 trial of cisplatin, methotrexate and vinblastine (CMV) for pure squamous cell cancer of the urinary tract
No full textBACKGROUND: Pure squamous cell carcinoma (SCC) of the urinary tract is rare in the UK and has a poor prognosis compared with transitional cell carcinoma (TCC). Cisplatin based chemotherapy has been shown to be effective in TCC. METHODS: Patients with T3-T4, pelvic relapsed, nodal or metastatic SCC of the urinary tract were recruited into an open-label, single-arm, non-randomised, phase 2 trial evaluating the activity and safety of cisplatin, methotrexate and vinblastine (CMV) chemotherapy. CMV was given as three 21-day cycles of methotrexate 30mg/m² (day 1 & 8), vinblastine 4mg/m² (day 1 & 8) and cisplatin 100mg/m² (day 2). RESULTS: 38 patients were recruited. Overall response was 39% (95% CI 24%, 55%)–13% CR and 26% PR. Median OS was 7.8 months (95% CI 3.4, 12.6) with 39% 1-year survival. Toxicity was acceptable. CONCLUSION: CMV is well tolerated and active in patients with pure SCC of the urinary tract
Toward semi-automated assessment of target volume delineation in radiotherapy trials: the SCOPE 1 pretrial test case
No full textPurpose: to evaluate different conformity indices (CIs) for use in the analysis of outlining consistency within the pretrial quality assurance (Radiotherapy Trials Quality Assurance [RTTQA]) program of a multicenter chemoradiation trial of esophageal cancer and to make recommendations for their use in future trials.Methods and materials: the National Cancer Research Institute SCOPE 1 trial is an ongoing Cancer Research UK-funded phase II/III randomized controlled trial of chemoradiation with capecitabine and cisplatin with or without cetuximab for esophageal cancer. The pretrial RTTQA program included a detailed radiotherapy protocol, an educational package, and a single mid-esophageal tumor test case that were sent to each investigator to outline. Investigator gross tumor volumes (GTVs) were received from 50 investigators in 34 UK centers, and CERR (Computational Environment for Radiotherapy Research) was used to perform an assessment of each investigator GTV against a predefined gold-standard GTV using different CIs. A new metric, the local conformity index (l-CI), that can localize areas of maximal discordance was developed.Results: the median Jaccard conformity index (JCI) was 0.69 (interquartile range, 0.62-0.70), with 14 of 50 investigators (28%) achieving a JCI of 0.7 or greater. The median geographical miss index was 0.09 (interquartile range, 0.06-0.16), and the mean discordance index was 0.27 (95% confidence interval, 0.25-0.30). The l-CI was highest in the middle section of the volume, where the tumor was bulky and more easily definable, and identified 4 slices where fewer than 20% of investigators achieved an l-CI of 0.7 or greater.Conclusions: the available CIs analyze different aspects of a gold standard-observer variation, with JCI being the most useful as a single metric. Additional information is provided by the l-CI and can focus the efforts of the RTTQA team in these areas, possibly leading to semi-automated outlining assessment.</p
Interim safety data on the FRAGMATIC trial: a randomised phase III clinical trial investigating the effect of FRAGMin (R) added to standard therapy in patients with lung cancer
No full textBackground: Venous thromboembolism (VTE) is common in lungcancer patients and the incidence is increased by treatments. Lungcancer patients often have advanced disease at presentation, as wellas co-morbidities, such as heart failure and chronic lung disease allof which increase the risk of VTE. Low molecular weight heparin(LMWH) has been used in the prophylaxis of VTE but there arelimited data on the use of LMWH as primary thromboprophylaxisin cancer patients. Because of this and interesting animal data suggestingthat LMWH may be anti-metastatic, the effect of long termLMWH on overall survival should be investigated
A single centre phase II trial to assess the immunological activity of TroVax® plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma – the SKOPOS trial
No full textVaccines in combination with chemotherapy have been shown to be safe in different tumor types. We investigated the immunological activity of the TroVax® vaccine in combination with pemetrexed-cisplatin chemotherapy in malignant pleural mesothelioma (MPM).In this first line, open-label, single-arm, phase 2 study, patients with locally advanced or metastatic MPM were enrolled. Eligible patients received up to 9 intramuscular injections of TroVax®, starting two weeks before chemotherapy and continuing at regular intervals during and after chemotherapy to 24 weeks. The primary endpoint was the induction of cellular or humoral anti-5T4 immune response (defined as a doubling of either response at any of six follow-up time points), with a target response rate of 64%.Of 27 patients, enrolled between Feb 2013-Dec 2014, 23 (85%) received at least three doses of TroVax® and one cycle of chemotherapy and were included in the per-protocol analysis (PPA). 22/23 patients (95.6%) developed humoral or cellular immune response to 5T4. Thus, the study reached its primary endpoint. Disease control was observed in 87% of patients (partial response: 17.4%, stable disease: 69.6%). The median progression-free survival was 6.8 months and median overall survival 10.9 months. Treatment-related adverse events were comparable to those observed in patients with chemotherapy alone. Translational immunology studies revealed a circulating baseline immune signature that was significantly associated with long-term (>20 months in n = 8/23, 34.8%) survival.In this phase 2 trial, TroVax® with pemetrexed-cisplatin chemotherapy showed robust immune activity, acceptable safety and tolerability to warrant further investigation in a phase 3 setting
Impact of short-course preoperative radiotherapy for rectal cancer on patients' quality of life::data From the Medical Research Council CR07/National Cancer Institute of Canada Clinical Trials Group C016 randomized clinical trial
No full textPurpose The Medical Research Council CR07/National Cancer Institute of Canada Clinical Trials Group C016 (MRC CR07/NCIC CTG C016) trial showed that, in patients with operable rectal cancer, short-course preoperative radiotherapy (PRE) reduced the rate of local recurrence compared with surgery followed by selective postoperative chemoradiotherapy for patients with a positive circumferential resection margin. However, the advantages of giving PRE to all patients needs to be balanced against any negative impact on patients' quality of life.Patients and Methods All 1,350 patients were asked to complete the Medical Outcomes Study Short-Form 36-item (MOS SF-36) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Colorectal 38-item (EORTC QLQ-CR38) questionnaires. A priori hypotheses related to the impact of treatment on sexual, bowel, and physical function and general health.Results Male sexual dysfunction was significantly increased following surgery (P < .001), although there was no difference between treatment arms. However, a treatment difference had emerged at 6 months (PRE patients reporting significantly greater dysfunction; P = .004), which persisted out to at least 2 years (an insufficient number of female patients completed the sexual dysfunction questions to draw firm conclusions). Both treatment groups reported similar levels of decreased physical function at 3 months, but thereafter it returned to baseline levels. There was no evidence of any major changes between treatments or time points in terms of general health or bowel function, but exploratory analysis indicated a significant (P = .006 at 2 years) increase in the level of fecal incontinence with PRE.Conclusion These results from a large randomized trial using validated patient-completed questionnaires show that, for males, the main adverse effect was sexual dysfunction, and the main cause of this was surgery, but that PRE also affected sexual and some aspects of bowel functioning.</p
Can p53 staining be used to identify patients with aggressive superficial bladder cancer?
No full textApproximately 10% of patients with superficial bladder cancer (pTa/pT1) recur with life-threatening muscle-invasive disease. Identification of these patients has been a major goal of bladder cancer research. In 1994, it was suggested that p53 immunostaining could identify the cancers that would progress and it was proposed that tumours that stain for p53 should be treated aggressively with radiotherapy or cystectomy. Despite the hundreds of studies published since on the relationship between p53 and progression in superficial bladder cancer, the clinical utility of p53 immunostaining has not been resolved because of limitations concerning the numbers of patients and the length of follow-up. This study set out to overcome these limitations by using tissue from a large multicentre trial that recruited 502 patients with a median follow-up of 10 years. Each of 34 patients that had progressed with >/= pT2 disease or had distant metastases or had died from bladder cancer was compared with one or two matched controls. Sections were stained with a mouse monoclonal antibody to p53, pAb1801. In agreement with many of the earlier studies, p53 immunostaining had prognostic significance. The adjusted hazard ratio for time to progression for the pAb1801-positive versus negative group was 2.5, with 95% confidence intervals of 1.05-5.98 (p = 0.039). The other major risk factor that is associated with progression of superficial bladder cancer is pT1G3 disease. Of the 42 pT1G3 cancers, 14 (33%) progressed. The proportion of cancers with p53 staining that progressed was similar to the proportion of pT1G3 cancers that progressed, but neither the sensitivity nor the specificity of association of p53 staining with progression is sufficient to recommend cystectomy in individual patients.</p
Monitoring of large randomised clinical trials: a new approach with Bayesian methods.
No full textBACKGROUND: In judging whether or not to continue enrolling patients into a randomised clinical trial, most data-monitoring and ethics committees (DMECs) rely on the p value for the difference in effect between the study groups. In the 1990s, two randomised controlled trials-one in patients with lung cancer and one in those with head and neck cancer-were instead monitored by Bayesian methods. We assessed the value of this approach in the monitoring of these clinical trials. METHODS: Before the trials opened, participating clinicians were asked their opinions on the expected difference between the study treatment (continuous hyperfractionated accelerated radiotherapy [CHART]) and conventional radiotherapy. These opinions were used to form an "enthusiastic" and a "sceptical" prior distribution. These prior distributions were combined with the trial data at each of the annual DMEC meetings. If, during monitoring, a result in favour of CHART was seen, the DMEC was to decide whether the results were sufficiently convincing to persuade a sceptic that CHART was worthwhile. Conversely, if there was apparently no or little difference, the DMEC was asked whether they thought the results sufficiently convincing to persuade an enthusiast that CHART was not worthwhile. FINDINGS: At each of the annual meetings, the DMEC concluded that there was insufficient evidence to convert either sceptics or enthusiasts, and that the trials should therefore remain open to recruitment. Neither trial was closed to recruitment earlier than planned. However if a conventional (p-value-based) stopping rule had been used, the lung-cancer trial would probably have been stopped. INTERPRETATION: This Bayesian approach to monitoring is simple to implement and straightforward for members of the DMEC to understand. In our opinion, it is more intuitively appealing than conventional approaches
Utilising pancreatic exocrine insufficiency in the detection of resectable pancreatic ductal adenocarcinoma
No full textPancreatic ductal adenocarcinoma (PDAC) is usually diagnosed late, leading to a high mortality rate. Early detection facilitates better treatment options. The aim of this UK-based case–control study was to determine whether two validated tests for pancreatic exocrine insufficiency (PEI), namely, the 13C-mixed triglyceride breath test (13C-MTGBT) and a faecal elastase (FE-1) test, can discriminate between patients with resectable PDAC versus healthy volunteers (HVs) along with a comparison group with chronic pancreatitis (CP). Discrimination between disease states and HVs was tested with receiver operator characteristic (ROC) curves. In total, 59 participants (23 PDAC (16 men), 24 HVs (13 men) and 12 CP (10 men)) were recruited, with a similar age in each population, and a combined median (IQR) age of 66 (57–71). The areas under the ROC curve for discriminating between PDAC and HVs were 0.83 (95% CI: 0.70–0.96) for the 13C-MTGBT, and 0.85 (95% CI: 0.75–0.95) for the FE-1 test. These were similar to CP vs. HV. In conclusion, PEI occurs in resectable PDAC to a similar extent as in CP; further large-scale, prospective studies using these tests in the primary care setting on high-risk groups are warranted
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