Taylor C.W.,Clinical Trial Service Unit |
Bronnum D.,Aarhus University Hospital |
Darby S.C.,Clinical Trial Service Unit |
Gagliardi G.,Karolinska University Hospital |
And 5 more authors.
Radiotherapy and Oncology | Year: 2011
Background and purpose: To estimate target and cardiac doses from breast cancer radiotherapy in Denmark and in the Stockholm and Ume areas of Sweden during 1977-2001. Methods: Representative samples of irradiated women were identified from the databases of the Danish Breast Cancer Cooperative Group and the Swedish Nationwide Cancer Registry. Virtual simulation, computed tomography planning and manual planning were used to reconstruct radiotherapy regimens on a typical woman. Estimates of target dose and various measures of cardiac dose were derived from individual radiotherapy charts. Results: Doses were estimated in 681 Danish and 130 Swedish women. Mean heart dose for individual women varied from 1.6 to 14.9 Gray in Denmark and from 1.2 to 22.1 Gray in Sweden. In Denmark, mean target doses averaged across women increased from 40.6 to 53.8 Gray during 1977-2001 but, despite this, mean heart dose averaged across women remained around 6 Gy for left-sided and 2-3 Gray for right-sided radiotherapy. In Sweden mean target dose averaged across women increased from 38.7 to 46.6 Gray during 1977-2001, while mean heart dose averaged across women decreased from 12.0 to 7.3 Gray for left-sided and from 3.6 to 3.2 Gray for right-sided radiotherapy. Temporal trends for mean biologically effective dose [BED] to the heart, mean dose to the left anterior descending coronary artery, the right coronary artery and the circumflex coronary artery were broadly similar. Conclusions: Cardiac doses in Denmark were low relative to those in Sweden. In both countries, target dose increased during 1977-2001. Despite this, cardiac doses remained constant in Denmark and decreased in Sweden. © 2011 Elsevier Ireland Ltd. All rights reserved.
News Article | November 7, 2016
DALLAS, Nov. 7, 2016 -- The age at which cancer survivors were diagnosed for cancer may help determine their risk of death from heart disease, according to new research in the American Heart Association's journal Circulation. Heart disease has been known to be the leading cause of treatment-related, non-tumor deaths among survivors of childhood cancer, breast cancer and Hodgkin lymphoma. As of now, the risk of cardiac mortality has not been investigated comprehensively within a large population of teenage and young adult cancer survivors, researchers say. The United Kingdom-based study consisted of more than 200,000 survivors diagnosed with cancer from ages 15 to 39 who survived at least five years after being diagnosed. Researchers examined data from these survivors and found: Six percent of deaths were caused by heart disease. Cancer survivors diagnosed at ages 15 to 19 had 4.2 times higher risk of death from heart disease compared to the general population of similar age and gender. Survivors who were 35 to 39 years old at cancer diagnosis had 1.2 times higher risk of death from heart disease compared to the general population of similar age and gender. "It is important for clinicians because it helps them focus the most intensive follow-up care on those most at risk," said Mike Hawkins, D.Phil., study senior author, epidemiology professor and director of the Centre for Childhood Cancer Survivor Studies at the University of Birmingham in England. "It is important for survivors because it empowers them by providing them with their long-term chances of a specific side effect of cancer treatment." The significance of age at diagnosis was most apparent for survivors of Hodgkin lymphoma - cancer of the lymphatic system. 6.9 percent of survivors who were diagnosed with Hodgkin lymphoma at ages 15-19 had died of heart disease by age 55 years compared to two percent of those diagnosed at ages 35-39. Given their age and gender less than one percent of these survivors would have been expected to die from general population rates. Survivors of Hodgkin lymphoma experienced 3.8 times the risk of death from heart disease than expected from members of the general population of similar age and gender. Among survivors of Hodgkin's lymphoma aged over 60 years, almost 28 percent of the total excess number of deaths observed were due to heart disease. Survivors of other types of cancer also had a higher than expected risk of death from heart disease including: leukemia, genitourinary cancer, lung cancer, breast cancer, and others. This new research provides insight into the cardiotoxicity of cancer treatments given in the past to teenagers and young adults - a growing topic of focus in medical circles related to cancer treatment. However, researchers noted the study lacks detailed information on exposure to cancer treatments: radiotherapy and chemotherapy. "Survivors of cancer diagnosed in teenage and young adulthood are internationally acknowledged to be an under studied population. With the advantage of long-standing cancer registration for the U.K. population, we were in a position to undertake the largest study to date, which has the advantage of being population-based and benefits from lengthy follow-up after diagnosis," Hawkins said. Participants were part of The Teenage and Young Adult Cancer Survivor Study of 200,945 cancer survivors diagnosed in England and Wales from 1971 to 2006 and followed to 2014. Co-authors are Katherine Henson, D.Phil; Raoul Reulen, Ph.D.; David Winter, H.N.C.; Chloe Bright, M.Sc.; Miranda Fidler, Ph.D.; Clare Frobisher, Ph.D.; Joyeeta Guha, Ph.D.; Kwok Wong, Ph.D.; Julie Kelly; Angela Edgar, M.D.; Martin McCabe, M.D., Ph.D.; Jeremy Whelan, M.D., F.R.C.P., M.B.B.S.; David Cutter, D.Phil; and Sarah Darby, Ph.D. Author disclosures are on the manuscript. Cancer Research U.K., the National Institute for Health Research, Department of Health Policy Research Programme, Nuffield Department of Population Health, Clinical Trial Service Unit and British Heart Foundation Centre for Research Excellence funded the study. Heart graphic is located in the right column of this release link http://newsroom. Statements and conclusions of study authors published in American Heart Association scientific journals are solely those of the study authors and do not necessarily reflect the association's policy or position. The association makes no representation or guarantee as to their accuracy or reliability. The association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific association programs and events. The association has strict policies to prevent these relationships from influencing the science content. Revenues from pharmaceutical and device corporations are available at http://www. .
Flint J.,Oxford Genetics |
Chen Y.,Clinical Trial Service Unit |
Shi S.,Fudan University |
Shi S.,Shanghai JiaoTong University |
Kendler K.S.,Virginia Commonwealth University
Journal of Affective Disorders | Year: 2012
This review summarizes the first clinical reports from the CONVERGE consortium: China, Oxford and VCU Experimental Research on Genetic Epidemiology. CONVERGE sets out to investigate the nature and mode of action of the genetic and environmental risk factors for major depressive disorder (MDD). CONVERGE aims to collect 6000 cases of recurrent MDD and 6000 controls. The consortium includes hospitals in 30 cities, all with populations exceeding 5 million, and has collected over 2000 cases and controls. High quality phenotype data on MDD collected in China is now available to determine the source and nature of this highly heterogeneous condition. Analyses reported in a series of papers indicate that the clinical features and risk factors of MDD are sufficiently similar to those in the West that we can confidently predict that the results of subsequent analyses will be widely applicable. © 2011 Elsevier B.V.
Dearden C.E.,Royal Marsden Hospital |
Richards S.,Clinical Trial Service Unit |
Else M.,Royal Marsden Hospital |
Catovsky D.,Royal Marsden Hospital |
Hillmen P.,Leeds Teaching Hospitals
Cancer | Year: 2011
BACKGROUND: An oral formulation of fludarabine was introduced for use in chronic lymphocytic leukemia in 2001 following studies demonstrating the bioequivalence of a 40 mg/m2 oral dose with a 25 mg/m2 intravenous dose. We assessed retrospectively the efficacy of these two routes of administration in the LRF CLL4 trial. METHODS: A total of 777 patients were randomized from 1999-2004 to receive fludarabine, alone or with cyclophosphamide, or chlorambucil. In 2001, a protocol amendment allowed the oral formulation. There were 117 assessable patients who received fludarabine intravenously and 252 who received it orally. A total of 387 patients given chlorambucil acted as a control group. RESULTS: Patients given oral fludarabine were less likely to receive the full dose (P = .0004) and experienced more, predominantly gastrointestinal, toxicity. Progression-free survival (PFS) and overall survival were not affected by the route of administration (PFS hazard ratio, 1.10; 95% confidence interval, 0.87-1.40), but the overall rate of response to treatment appeared to be lower with the oral formulation (P = .003). However, patients recruited since 2001 were older (P = .03) and were more likely to have TP53 deletion, and response rates after 2001 were also lower in the chlorambucil group. After excluding patients with TP53 deletion, no significant difference in outcome was attributable to the route of administration. CONCLUSIONS: Although the LRF CLL4 data suggest no important difference in the effectiveness of oral compared with intravenous fludarabine, randomized trials are needed to reliably evaluate this comparison, particularly in combination with rituximab. Meanwhile, it is important to monitor compliance and gastrointestinal side effects with the oral route and to switch to intravenous therapy if a reduced dose is being received. © 2010 American Cancer Society.
Fielding A.K.,University College London |
Rowe J.M.,Rambam Medical Center |
Buck G.,Clinical Trial Service Unit |
Foroni L.,Imperial College London |
And 11 more authors.
Blood | Year: 2014
The Philadelphia chromosome positive arm of the UKALLXII/ECOG2993 study for adult acute lymphoblastic leukemia (ALL) enrolled 266 patients between 1993 and 2003 (preimatinib cohort). In 2003 imatinib was introduced as a single-agent course following induction (N 5 86, late imatinib). In 2005 imatinib was added to the second phase of induction (N 5 89, early imatinib). The complete remission (CR) rate was 92% in the imatinib cohort vs 82% in the preimatinib cohort (P 5 .004). At 4 years, the overall survival (OS) of all patients in the imatinib cohort was 38% vs 22% in the preimatinib cohort (P 5 .003). The magnitude of the difference between the preimatinib and imatinib cohorts in event-free survival (EFS), OS, and relapse-free survival (RFS) seen in univariate analysis was even greater in the multivariate analysis. In the preimatinib cohort, 31% of those starting treatment achieved hematopoietic stem cell transplant (alloHSCT) compared with 46% in the imatinib cohort. A Cox multivariate analysis taking alloHSCT into account showed a modest additional benefit to imatinib (hazard ratio for EFS 5 0.64, 95% confidence interval 0.44-0.93, P 5 .02), but no significant benefit for OS and RFS. Adding imatinib to standard therapy improves CR rate and long-term OS for adults with ALL. A proportion of the OS benefit derives from the fact that imatinib facilitates alloHSCT. This trial was registered at clinicaltrials.gov as NCT00002514. © 2014 by The American Society of Hematology.
News Article | September 8, 2016
LONDON, (Reuters) - - The benefits of statins - cholesterol-busting drugs that can dramatically reduce the risk of heart attacks and strokes - have been underestimated and their harms exaggerated, scientists said on Thursday in a major review of research. In an effort to counter what they said were misleading reports of high levels of side effects, the scientists said in the Lancet medical journal there was a "serious cost to public health" in such claims, which can dissuade people from taking beneficial medicines. "Our review shows that the numbers of people who avoid heart attacks and strokes by taking statin therapy are very much larger than the numbers who have side effects," said Rory Collins, a professor at the Clinical Trial Service Unit at Britain's Oxford University. He also said that those who experience side effects -- which include muscle pain, nausea and liver problems -- could reverse them by stopping the statin, while the effects of a heart attack or stroke "are irreversible and can be devastating". Once among the biggest revenue generators for drugmakers such as Pfizer and AstraZeneca, most statins are now off-patent and available as cheap generics. U.S. health guidelines recommend aggressive statin therapy for high-risk patients. In Britain, they are taken by an estimated 7 million people and health authorities have said they should be prescribed more widely as preventatives. Cardiovascular diseases such as heart attacks and strokes are the world's number one killers, accounting for an estimated 31 percent of all deaths and claiming 17.5 million lives a year worldwide, according to the World Health Organization. A row over statins erupted in Britain in 2013 when the British Medical Journal published papers by Harvard Medical School's John Abramson and UK cardiologist Aseem Malhotra claiming up to 20 percent of users get side effects. The 20 percent figure was later retracted after the BMJ said it was based on flawed data, but this and other reports affected patient confidence. In their review, Collins' team found that periods of intense public discussion about statins were followed by rises in the proportion of people who stop taking the drugs, and by falls in the number of prescriptions for them. As well as in Britain, studies in Denmark, Australia, Turkey and France have suggested that media debate about side effects of statins has led to measurable effects on their use. David Webb, president of the British Pharmacological Society, said he feared many patients who should take statins had been persuaded against them by exaggerated claims of harm: "It is likely that many lives have been lost based on a received view that statins are dangerous and ineffective," he said. The review found that lowering cholesterol by 2 millimoles per liter with a statin, such as a daily 40 milligram tablet of atorvastatin for 5 years in 10,000 patients would prevent major cardiovascular events in 1,500 people and cause problematic side effects in around 200.
Friend P.,Clinical Trial Service Unit
The Lancet | Year: 2014
Background Calcineurin inhibitors (CNIs) reduce short-term kidney transplant failure, but might contribute to transplant failure in the long-term. The role of alemtuzumab (a potent lymphocyte-depleting antibody) as an induction treatment followed by an early reduction in CNI and mycophenolate exposure and steroid avoidance, after kidney transplantation is uncertain. We aimed to assess the efficacy and safety of alemtuzumab-based induction treatment compared with basiliximab-based induction treatment in patients receiving kidney transplants. Methods For this randomised trial, we enrolled patients aged 18 years and older who were scheduled to receive a kidney transplant in the next 24 h from 18 transplant centres in the UK. Using minimised randomisation, we randomly assigned patients (1:1; minimised for age, sex, and immunological risk) to either alemtuzumab-based induction treatment (ie, alemtuzumab followed by low-dose tacrolimus and mycophenolate without steroids) or basiliximab-based induction treatment (basiliximab followed by standard-dose tacrolimus, mycophenolate, and prednisolone). Participants were reviewed at discharge from hospital and at 1, 3, 6, 9, and 12 months after transplantation. The primary outcome was biopsy-proven acute rejection at 6 months, analysed by intention to treat. The study is registered at ClinicalTrials.gov, number NCT01120028, and isrctn.org, number ISRCTN88894088. Findings Between Oct 4, 2010, and Jan 21, 2013, we randomly assigned 852 participants to treatment: 426 to alemtuzumab-based treatment and 426 to basiliximab-based treatment. Overall, individuals allocated to alemtuzumab-based treatment had a 58% proportional reduction in biopsy-proven acute rejection compared with those allocated to basiliximab-based treatment (31 [7%] patients in the alemtuzumab group vs 68 [16%] patients in the basiliximab group; hazard ratio (HR) 0·42, 95% CI 0·28-0·64; log-rank p<0·0001). We detected no between-group difference in treatment effect on transplant failure during the first 6 months (16 [4%] patients vs 13 [3%] patients; HR 1·23, 0·59-2·55; p=0·58) or serious infection (135 [32%] patients vs 136 [32%] patients; HR 1·02, 0·80-1·29; p=0·88). During the first 6 months after transplantation, 11 (3%) patients given alemtuzumab-based treatment and six (1%) patients given basiliximab-based treatment died (HR 1·79, 95% CI 0·66-4·83; p=0·25). Interpretation Compared with standard basiliximab-based treatment, alemtuzumab-based induction therapy followed by reduced CNI and mycophenolate exposure and steroid avoidance reduced the risk of biopsy-proven acute rejection in a broad range of patients receiving a kidney transplant. Long-term follow-up of this trial will assess whether these effects translate into differences in long-term transplant function and survival. Funding UK National Health Service Blood and Transplant Research and Development Programme, Pfizer, and Novartis UK. © 2014 Elsevier Ltd.
Catovsky D.,Institute of Cancer Research |
Else M.,Institute of Cancer Research |
Richards S.,Clinical Trial Service Unit
Clinical Lymphoma, Myeloma and Leukemia | Year: 2011
Although chlorambucil has been used in the management of chronic lymphocytic leukemia (CLL) for 55 years, the optimal dose and treatment duration have not been established. We summarized data from 4 UK randomized CLL trials over the past 30 years in which chlorambucil, as a single agent, was one of the study arms. Overall response rates (ORR) ranged from 57% to 75% when using doses of 60-70 mg/m 2 per 28-day cycle. This compares favorably with an ORR of 31% to 55% in other studies that used lower doses. Response rates improved when patients received 6 or more courses. Studies that used chlorambucil as a comparator, at lower doses or with fewer courses, resulted in consistently lower ORR. Comparisons with single-agent fludarabine in 2 randomized trials (LRF CLL4 and German CLL5) showed similar progression-free survival. Chlorambucil compares favorably with fludarabine and bendamustine with respect to myelotoxicity, neutropenia, and fever, even at 70 mg/m2 per cycle and in the elderly. Resistance to chlorambucil does not preclude a good response to newer treatments used as second-line treatment, which explains the good survival after progression observed in patients randomized to chlorambucil in LRF CLL4. Chlorambucil is currently being combined with anti-CD20 monoclonal antibodies in several phase II and III trials. It remains a useful drug for patients unfit to receive more intensive combinations. However, both the dose and duration of treatment are important. © 2011 Published by Elsevier Inc.
Taylor C.W.,Clinical Trial Service Unit |
Kirby A.M.,Royal Marsden NHS Foundation Trust
Clinical Oncology | Year: 2015
Breast cancer radiotherapy reduces the risk of cancer recurrence and death. However, it usually involves some radiation exposure of the heart and analyses of randomised trials have shown that it can increase the risk of heart disease. Estimates of the absolute risks of radiation-related heart disease are needed to help oncologists plan each individual woman's treatment. The risk for an individual woman varies according to her estimated cardiac radiation dose and her background risk of ischaemic heart disease in the absence of radiotherapy. When it is known, this risk can then be compared with the absolute benefit of the radiotherapy. At present, many UK cancer centres are already giving radiotherapy with mean heart doses of less than 3 Gy and for most women the benefits of the radiotherapy will probably far outweigh the risks. Technical approaches to minimising heart dose in breast cancer radiotherapy include optimisation of beam angles, use of multileaf collimator shielding, intensity-modulated radiotherapy, treatment in a prone position, treatment in deep inspiration (including the use of breath-hold and gating techniques), proton therapy and partial breast irradiation. The multileaf collimator is suitable for many women with upper pole left breast cancers, but for women with central or lower pole cancers, breath-holding techniques are now recommended in national UK guidelines. Ongoing work aims to identify ways of irradiating pan-regional lymph nodes that are effective, involve minimal exposure of organs at risk and are feasible to plan, deliver and verify. These will probably include wide tangent-based field-in-field intensity-modulated radiotherapy or arc radiotherapy techniques in combination with deep inspiratory breath-hold, and proton beam irradiation for women who have a high predicted heart dose from intensity-modulated radiotherapy. © 2015 The Royal College of Radiologists.
Catovsky D.,The Institute of Cancer Research |
Wade R.,Clinical Trial Service Unit |
Else M.,The Institute of Cancer Research
Haematologica | Year: 2014
We examined the prognostic influence of gender in chronic lymphocytic leukemia. Data from four randomized trials (involving 1821 patients) and three registration studies of stage-A disease (involving 1299 patients) were analyzed. Overall survival at 10 years was better for women than men in all trials (27% versus 15%; P=0.0001) and in the registration series (55% versus 43%; P<0.0001). More women than men in the trials were Binet stage A-progressive (26% versus 15%), but gender was an independent predictor of survival in multivariate analysis of clinical variables (P<0.0001). Women responded better to treatment (overall response 83%) than men (71%; P<0.0001), within each stage and age group, although fewer women than men received the full treatment dose (79% versus 85%; P=0.01). Women were more likely than men to experience toxicity (85% versus 78%, P=0.01), particularly gastro-intestinal toxicity (57% versus 42%, P<0.0001). Laboratory markers in the LRF CLL4 trial showed a significantly lower incidence in women than men of unmutated IGHV genes, raised beta-2 microglobulin, CD38 and Zap-70 positivity and TP53 deletions/mutations and/or 11q deletions. We also highlight the higher male:female ratios in randomized trials versus studies of early chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. Chronic lymphocytic leukemia in women runs a more benign clinical course than in men. Gender was also an independent predictor of response, suggesting that pharmacokinetic differences between the sexes and a possible effect of estrogens may contribute to the better outcome. Understanding the reasons for the different outcome by gender may improve patients' management. (LRF CLL4 controlled-trials.com identifier: ISRCTN58585610). © 2014 Ferrata Storti Foundation.