Paul McGale

University of Melbourne, Melbourne, Victoria, Australia

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Publications (43)812.09 Total impact

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    ABSTRACT: Background Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer. Methods We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs). Findings We received data on 18 766 women (18 206 [97%] in trials of 2-5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73-0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75-0·97; 2p=0·02). Interpretation Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began. Funding Cancer Research UK, Medical Research Council.
    Full-text · Article · Oct 2015 · The Lancet
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    Paul McGale · Carolyn Taylor · Sarah Darby

    Preview · Article · Jun 2015
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    Full-text · Article · Apr 2015
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    ABSTRACT: Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials EBCTCG (Early Breast Cancer Trialists' Collaborative Group)* Summary Background Postmastectomy radiotherapy was shown in previous meta-analyses to reduce the risks of both recurrence and breast cancer mortality in all women with node-positive disease considered together. However, the benefi t in women with only one to three positive lymph nodes is uncertain. We aimed to assess the eff ect of radiotherapy in these women after mastectomy and axillary dissection. Methods We did a meta-analysis of individual data for 8135 women randomly assigned to treatment groups during 1964–86 in 22 trials of radiotherapy to the chest wall and regional lymph nodes after mastectomy and axillary surgery versus the same surgery but no radiotherapy. Follow-up lasted 10 years for recurrence and to Jan 1, 2009, for mortality. Analyses were stratifi ed by trial, individual follow-up year, age at entry, and pathological nodal status. Findings 3786 women had axillary dissection to at least level II and had zero, one to three, or four or more positive nodes. All were in trials in which radiotherapy included the chest wall, supraclavicular or axillary fossa (or both), and internal mammary chain. For 700 women with axillary dissection and no positive nodes, radiotherapy had no signifi cant eff ect on locoregional recurrence (two-sided signifi cance level [2p]>0·1), overall recurrence (rate ratio [RR], irradiated vs not, 1·06, 95% CI 0·76–1·48, 2p>0·1), or breast cancer mortality (RR 1·18, 95% CI 0·89–1·55, 2p>0·1). For 1314 women with axillary dissection and one to three positive nodes, radiotherapy reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·68, 95% CI 0·57–0·82, 2p=0·00006), and breast cancer mortality (RR 0·80, 95% CI 0·67–0·95, 2p=0·01). 1133 of these 1314 women were in trials in which systemic therapy (cyclophosphamide, methotrexate, and fl uorouracil, or tamoxifen) was given in both trial groups and, for them, radiotherapy again reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·67, 95% CI 0·55–0·82, 2p=0·00009), and breast cancer mortality (RR 0·78, 95% CI 0·64–0·94, 2p=0·01). For 1772 women with axillary dissection and four or more positive nodes, radiotherapy reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·79, 95% CI 0·69–0·90, 2p=0·0003), and breast cancer mortality (RR 0·87, 95% CI 0·77–0·99, 2p=0·04). Interpretation After mastectomy and axillary dissection, radiotherapy reduced both recurrence and breast cancer mortality in the women with one to three positive lymph nodes in these trials even when systemic therapy was given. For today's women, who in many countries are at lower risk of recurrence, absolute gains might be smaller but proportional gains might be larger because of more effective radiotherapy.
    Full-text · Article · Jun 2014 · The Lancet
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    ABSTRACT: Postmastectomy radiotherapy was shown in previous meta-analyses to reduce the risks of both recurrence and breast cancer mortality in all women with node-positive disease considered together. However, the benefit in women with only one to three positive lymph nodes is uncertain. We aimed to assess the effect of radiotherapy in these women after mastectomy and axillary dissection. We did a meta-analysis of individual data for 8135 women randomly assigned to treatment groups during 1964-86 in 22 trials of radiotherapy to the chest wall and regional lymph nodes after mastectomy and axillary surgery versus the same surgery but no radiotherapy. Follow-up lasted 10 years for recurrence and to Jan 1, 2009, for mortality. Analyses were stratified by trial, individual follow-up year, age at entry, and pathological nodal status. 3786 women had axillary dissection to at least level II and had zero, one to three, or four or more positive nodes. All were in trials in which radiotherapy included the chest wall, supraclavicular or axillary fossa (or both), and internal mammary chain. For 700 women with axillary dissection and no positive nodes, radiotherapy had no significant effect on locoregional recurrence (two-sided significance level [2p]>0·1), overall recurrence (rate ratio [RR], irradiated vs not, 1·06, 95% CI 0·76-1·48, 2p>0·1), or breast cancer mortality (RR 1·18, 95% CI 0·89-1·55, 2p>0·1). For 1314 women with axillary dissection and one to three positive nodes, radiotherapy reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·68, 95% CI 0·57-0·82, 2p=0·00006), and breast cancer mortality (RR 0·80, 95% CI 0·67-0·95, 2p=0·01). 1133 of these 1314 women were in trials in which systemic therapy (cyclophosphamide, methotrexate, and fluorouracil, or tamoxifen) was given in both trial groups and, for them, radiotherapy again reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·67, 95% CI 0·55-0·82, 2p=0·00009), and breast cancer mortality (RR 0·78, 95% CI 0·64-0·94, 2p=0·01). For 1772 women with axillary dissection and four or more positive nodes, radiotherapy reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·79, 95% CI 0·69-0·90, 2p=0·0003), and breast cancer mortality (RR 0·87, 95% CI 0·77-0·99, 2p=0·04). After mastectomy and axillary dissection, radiotherapy reduced both recurrence and breast cancer mortality in the women with one to three positive lymph nodes in these trials even when systemic therapy was given. For today's women, who in many countries are at lower risk of recurrence, absolute gains might be smaller but proportional gains might be larger because of more effective radiotherapy. Cancer Research UK, British Heart Foundation, UK Medical Research Council.
    Full-text · Article · Mar 2014 · The Lancet
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    ABSTRACT: To assess the cancer risk in children and adolescents following exposure to low dose ionising radiation from diagnostic computed tomography (CT) scans. DESIGN : Population based, cohort, data linkage study in Australia. COHORT MEMBERS: 10.9 million people identified from Australian Medicare records, aged 0-19 years on 1 January 1985 or born between 1 January 1985 and 31 December 2005; all exposures to CT scans funded by Medicare during 1985-2005 were identified for this cohort. Cancers diagnosed in cohort members up to 31 December 2007 were obtained through linkage to national cancer records. Cancer incidence rates in individuals exposed to a CT scan more than one year before any cancer diagnosis, compared with cancer incidence rates in unexposed individuals. 60 674 cancers were recorded, including 3150 in 680 211 people exposed to a CT scan at least one year before any cancer diagnosis. The mean duration of follow-up after exposure was 9.5 years. Overall cancer incidence was 24% greater for exposed than for unexposed people, after accounting for age, sex, and year of birth (incidence rate ratio (IRR) 1.24 (95% confidence interval 1.20 to 1.29); P<0.001). We saw a dose-response relation, and the IRR increased by 0.16 (0.13 to 0.19) for each additional CT scan. The IRR was greater after exposure at younger ages (P<0.001 for trend). At 1-4, 5-9, 10-14, and 15 or more years since first exposure, IRRs were 1.35 (1.25 to 1.45), 1.25 (1.17 to 1.34), 1.14 (1.06 to 1.22), and 1.24 (1.14 to 1.34), respectively. The IRR increased significantly for many types of solid cancer (digestive organs, melanoma, soft tissue, female genital, urinary tract, brain, and thyroid); leukaemia, myelodysplasia, and some other lymphoid cancers. There was an excess of 608 cancers in people exposed to CT scans (147 brain, 356 other solid, 48 leukaemia or myelodysplasia, and 57 other lymphoid). The absolute excess incidence rate for all cancers combined was 9.38 per 100 000 person years at risk, as of 31 December 2007. The average effective radiation dose per scan was estimated as 4.5 mSv. The increased incidence of cancer after CT scan exposure in this cohort was mostly due to irradiation. Because the cancer excess was still continuing at the end of follow-up, the eventual lifetime risk from CT scans cannot yet be determined. Radiation doses from contemporary CT scans are likely to be lower than those in 1985-2005, but some increase in cancer risk is still likely from current scans. Future CT scans should be limited to situations where there is a definite clinical indication, with every scan optimised to provide a diagnostic CT image at the lowest possible radiation dose.
    Full-text · Article · May 2013 · BMJ (online)
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    ABSTRACT: Objective To assess the cancer risk in children and adolescents following exposure to low dose ionising radiation from diagnostic computed tomography (CT) scans. Design Population based, cohort, data linkage study in Australia. Cohort members 10.9 million people identified from Australian Medicare records, aged 0-19 years on 1 January 1985 or born between 1 January 1985 and 31 December 2005; all exposures to CT scans funded by Medicare during 1985-2005 were identified for this cohort. Cancers diagnosed in cohort members up to 31 December 2007 were obtained through linkage to national cancer records. Main outcome Cancer incidence rates in individuals exposed to a CT scan more than one year before any cancer diagnosis, compared with cancer incidence rates in unexposed individuals. Results 60 674 cancers were recorded, including 3150 in 680 211 people exposed to a CT scan at least one year before any cancer diagnosis. The mean duration of follow-up after exposure was 9.5 years. Overall cancer incidence was 24% greater for exposed than for unexposed people, after accounting for age, sex, and year of birth (incidence rate ratio (IRR) 1.24 (95% confidence interval 1.20 to 1.29); P<0.001). We saw a dose-response relation, and the IRR increased by 0.16 (0.13 to 0.19) for each additional CT scan. The IRR was greater after exposure at younger ages (P<0.001 for trend). At 1-4, 5-9, 10-14, and 15 or more years since first exposure, IRRs were 1.35 (1.25 to 1.45), 1.25 (1.17 to 1.34), 1.14 (1.06 to 1.22), and 1.24 (1.14 to 1.34), respectively. The IRR increased significantly for many types of solid cancer (digestive organs, melanoma, soft tissue, female genital, urinary tract, brain, and thyroid); leukaemia, myelodysplasia, and some other lymphoid cancers. There was an excess of 608 cancers in people exposed to CT scans (147 brain, 356 other solid, 48 leukaemia or myelodysplasia, and 57 other lymphoid). The absolute excess incidence rate for all cancers combined was 9.38 per 100 000 person years at risk, as of 31 December 2007. The average effective radiation dose per scan was estimated as 4.5 mSv. Conclusions The increased incidence of cancer after CT scan exposure in this cohort was mostly due to irradiation. Because the cancer excess was still continuing at the end of follow-up, the eventual lifetime risk from CT scans cannot yet be determined. Radiation doses from contemporary CT scans are likely to be lower than those in 1985-2005, but some increase in cancer risk is still likely from current scans. Future CT scans should be limited to situations where there is a definite clinical indication, with every scan optimised to provide a diagnostic CT image at the lowest possible radiation dose.
    Full-text · Article · May 2013 · BMJ (online)
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    ABSTRACT: Radiotherapy for breast cancer often involves some incidental exposure of the heart to ionizing radiation. The effect of this exposure on the subsequent risk of ischemic heart disease is uncertain. We conducted a population-based case-control study of major coronary events (i.e., myocardial infarction, coronary revascularization, or death from ischemic heart disease) in 2168 women who underwent radiotherapy for breast cancer between 1958 and 2001 in Sweden and Denmark; the study included 963 women with major coronary events and 1205 controls. Individual patient information was obtained from hospital records. For each woman, the mean radiation doses to the whole heart and to the left anterior descending coronary artery were estimated from her radiotherapy chart. The overall average of the mean doses to the whole heart was 4.9 Gy (range, 0.03 to 27.72). Rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray (95% confidence interval, 2.9 to 14.5; P<0.001), with no apparent threshold. The increase started within the first 5 years after radiotherapy and continued into the third decade after radiotherapy. The proportional increase in the rate of major coronary events per gray was similar in women with and women without cardiac risk factors at the time of radiotherapy. Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease. The increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years. Women with preexisting cardiac risk factors have greater absolute increases in risk from radiotherapy than other women. (Funded by Cancer Research UK and others.).
    Full-text · Article · Mar 2013 · New England Journal of Medicine
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    C.W. Taylor · P. McGale · S.C. Darby

    Preview · Article · Mar 2013
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    Full-text · Dataset · Jan 2013
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    K E Henson · P McGale · C Taylor · S C Darby
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    ABSTRACT: Background: Radiation-related heart disease and lung cancer can occur following radiotherapy for breast cancer but the duration of any mortality risk is uncertain. Methods: Mortality ratios, by laterality of breast cancer, were estimated using Poisson regression for 558 871 women recorded with breast cancer during 1973–2008 in the Surveillance, Epidemiology and End Results (SEER) cancer registries and followed until 01 January 2009. Results: For women diagnosed with breast cancer during 1973–1982 and given radiotherapy shortly afterwards, the cardiac mortality ratios, left-sided vs right-sided, were 1.19 (1.03–1.38), 1.35 (1.05–1.73), 1.64 (1.26–2.14) and 1.90 (1.52–2.37) at <10, 10–14, 15–19 and 20+ years since diagnosis (2p for trend: <0.001). The lung cancer mortality ratios, ipsilateral vs contralateral, in these women were 1.05 (0.57–1.94), 2.04 (1.28–3.23) and 3.87 (2.19–6.82) at <10, 10–19 and 20+ years, respectively, (2p for trend: 0.002). For women irradiated during 1983–92 there was evidence of radiation-related mortality for lung cancer, but not for heart disease. For women irradiated since 1993 there is, as yet, little evidence of any radiation-related mortality. Conclusion: In this population, the radiation-related risks were larger in the third decade after exposure than during the first two decades.
    Preview · Article · Dec 2012 · British Journal of Cancer
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    ABSTRACT: Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children. Bill & Melinda Gates Foundation.
    Full-text · Article · Dec 2012 · The Lancet
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    R Sakata · P McGale · E J Grant · K Ozasa · R Peto · S C Darby
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    ABSTRACT: To investigate the impact of smoking on overall mortality and life expectancy in a large Japanese population, including some who smoked throughout adult life. The Life Span Study, a population-based prospective study, initiated in 1950. Hiroshima and Nagasaki, Japan. Smoking status for 27 311 men and 40 662 women was obtained during 1963-92. Mortality from one year after first ascertainment of smoking status until 1 January 2008 has been analysed. Mortality from all causes in current, former, and never smokers. Smokers born in later decades tended to smoke more cigarettes per day than those born earlier, and to have started smoking at a younger age. Among those born during 1920-45 (median 1933) and who started smoking before age 20 years, men smoked on average 23 cigarettes/day, while women smoked 17 cigarettes/day, and, for those who continued smoking, overall mortality was more than doubled in both sexes (rate ratios versus never smokers: men 2.21 (95% confidence interval 1.97 to 2.48), women 2.61 (1.98 to 3.44)) and life expectancy was reduced by almost a decade (8 years for men, 10 years for women). Those who stopped smoking before age 35 avoided almost all of the excess risk among continuing smokers, while those who stopped smoking before age 45 avoided most of it. The lower smoking related hazards reported previously in Japan may have been due to earlier birth cohorts starting to smoke when older and smoking fewer cigarettes per day. In Japan, as elsewhere, those who start smoking in early adult life and continue smoking lose on average about a decade of life. Much of the risk can, however, be avoided by giving up smoking before age 35, and preferably well before age 35.
    Full-text · Article · Oct 2012 · BMJ (online)

  • No preview · Article · Feb 2012 · Cancer Research
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    ABSTRACT: Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences. We undertook individual-patient-data meta-analyses of the randomised trials comparing: any taxane-plus-anthracycline-based regimen versus the same, or more, non-taxane chemotherapy (n=44,000); one anthracycline-based regimen versus another (n=7000) or versus cyclophosphamide, methotrexate, and fluorouracil (CMF; n=18,000); and polychemotherapy versus no chemotherapy (n=32,000). The scheduled dosages of these three drugs and of the anthracyclines doxorubicin (A) and epirubicin (E) were used to define standard CMF, standard 4AC, and CAF and CEF. Log-rank breast cancer mortality rate ratios (RRs) are reported. In trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0·86, SE 0·04, two-sided significance [2p]=0·0005). In trials with four such extra cycles of a taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling non-taxane dosage, there was no significant difference (RR 0·94, SE 0·06, 2p=0·33). Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (RR 0·98, SE 0·05, 2p=0·67), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (eg, CAF or CEF) were superior to standard CMF (RR 0·78, SE 0·06, 2p=0·0004). Trials versus no chemotherapy also suggested greater mortality reductions with CAF (RR 0·64, SE 0·09, 2p<0·0001) than with standard 4AC (RR 0·78, SE 0·09, 2p=0·01) or standard CMF (RR 0·76, SE 0·05, 2p<0·0001). In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall mortality differences paralleled breast cancer mortality differences, despite taxane, anthracycline, and other toxicities. 10-year gains from a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute benefit, but information was lacking about tumour gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both. Cancer Research UK; British Heart Foundation; UK Medical Research Council.
    Full-text · Article · Dec 2011 · The Lancet
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    ABSTRACT: After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk. We undertook a meta-analysis of individual patient data for 10,801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease. Overall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 35·0% to 19·3% (absolute reduction 15·7%, 95% CI 13·7-17·7, 2p<0·00001) and reduced the 15-year risk of breast cancer death from 25·2% to 21·4% (absolute reduction 3·8%, 1·6-6·0, 2p=0·00005). In women with pN0 disease (n=7287), radiotherapy reduced these risks from 31·0% to 15·6% (absolute recurrence reduction 15·4%, 13·2-17·6, 2p<0·00001) and from 20·5% to 17·2% (absolute mortality reduction 3·3%, 0·8-5·8, 2p=0·005), respectively. In these women with pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and these characteristics were used to predict large (≥20%), intermediate (10-19%), or lower (<10%) absolute reductions in the 10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 7·8% (95% CI 3·1-12·5), 1·1% (-2·0 to 4·2), and 0·1% (-7·5 to 7·7) respectively (trend in absolute mortality reduction 2p=0·03). In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 63·7% to 42·5% (absolute reduction 21·2%, 95% CI 14·5-27·9, 2p<0·00001) and the 15-year risk of breast cancer death from 51·3% to 42·8% (absolute reduction 8·5%, 1·8-15·2, 2p=0·01). Overall, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease. After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of women. By contrast, the absolute benefits from radiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made. Cancer Research UK, British Heart Foundation, and UK Medical Research Council.
    Full-text · Article · Nov 2011 · The Lancet
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    ABSTRACT: As trials of 5 years of tamoxifen in early breast cancer mature, the relevance of hormone receptor measurements (and other patient characteristics) to long-term outcome can be assessed increasingly reliably. We report updated meta-analyses of the trials of 5 years of adjuvant tamoxifen. We undertook a collaborative meta-analysis of individual patient data from 20 trials (n=21,457) in early breast cancer of about 5 years of tamoxifen versus no adjuvant tamoxifen, with about 80% compliance. Recurrence and death rate ratios (RRs) were from log-rank analyses by allocated treatment. In oestrogen receptor (ER)-positive disease (n=10,645), allocation to about 5 years of tamoxifen substantially reduced recurrence rates throughout the first 10 years (RR 0·53 [SE 0·03] during years 0-4 and RR 0·68 [0·06] during years 5-9 [both 2p<0·00001]; but RR 0·97 [0·10] during years 10-14, suggesting no further gain or loss after year 10). Even in marginally ER-positive disease (10-19 fmol/mg cytosol protein) the recurrence reduction was substantial (RR 0·67 [0·08]). In ER-positive disease, the RR was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Breast cancer mortality was reduced by about a third throughout the first 15 years (RR 0·71 [0·05] during years 0-4, 0·66 [0·05] during years 5-9, and 0·68 [0·08] during years 10-14; p<0·0001 for extra mortality reduction during each separate time period). Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years), so all-cause mortality was substantially reduced. In ER-negative disease, tamoxifen had little or no effect on breast cancer recurrence or mortality. 5 years of adjuvant tamoxifen safely reduces 15-year risks of breast cancer recurrence and death. ER status was the only recorded factor importantly predictive of the proportional reductions. Hence, the absolute risk reductions produced by tamoxifen depend on the absolute breast cancer risks (after any chemotherapy) without tamoxifen. Cancer Research UK, British Heart Foundation, and Medical Research Council.
    Full-text · Article · Jul 2011 · The Lancet
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    ABSTRACT: To study incidence of radiation-related heart disease in a large population of breast cancer patients followed for up to 30 years. 72,134 women diagnosed with breast cancer in Denmark or Sweden during 1976-2006 and followed prospectively. Radiation-related risk was studied by comparing women with left-sided and right-sided tumours. 34,825 women (48%) received radiotherapy. Among unirradiated women tumour laterality had little relevance to heart disease. Among irradiated women mean dose to the whole heart was 6.3 Gy for left-sided tumours and 2.7 Gy for right-sided tumours. Mortality was similar in irradiated women with left-sided and right-sided tumours, but incidence ratios, left-sided versus right-sided, were raised: acute myocardial infarction 1.22 (95% CI 1.06-1.42), angina 1.25 (1.05-1.49), pericarditis 1.61 (1.06-2.43), valvular heart disease 1.54 (1.11-2.13). Incidence ratios for all heart disease were as high for women irradiated since 1990 (1.09 [1.00-1.19]) as for women irradiated during 1976-1989 (1.08 [0.99-1.17]), and were higher for women diagnosed with ischaemic heart disease prior to breast cancer than for other women (1.58 [1.19-2.10] versus 1.08 [1.01-1.15], p for difference=0.01). Breast cancer radiotherapy has, at least until recently, increased the risk of developing ischaemic heart disease, pericarditis and valvular disease. Women with ischaemic heart disease before breast cancer diagnosis may have incurred higher risks than others.
    No preview · Article · Jul 2011 · Radiotherapy and Oncology
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    ABSTRACT: Objective To examine whether statins can reduce the risk of atrial fibrillation. Design Meta-analysis of published and unpublished results from larger scale statin trials, with comparison of the findings against the published results from smaller scale or shorter duration studies. Data sources Medline, Embase, and Cochrane's CENTRAL up to October 2010. Unpublished data from longer term trials were obtained through contact with investigators. Study selection Randomised controlled trials comparing statin with no statin or comparing high dose versus standard dose statin; all longer term trials had at least 100 participants and at least six months' follow-up. Results In published data from 13 short term trials (4414 randomised patients, 659 events), statin treatment seemed to reduce the odds of an episode of atrial fibrillation by 39% (odds ratio 0.61, 95% confidence interval 0.51 to 0.74; P<0.001), but there was significant heterogeneity (P<0.001) between the trials. In contrast, among 22 longer term and mostly larger trials of statin versus control (105 791 randomised patients, 2535 events), statin treatment was not associated with a significant reduction in atrial fibrillation (0.95, 0.88 to 1.03; P=0.24) (P<0.001 for test of difference between the two sets of trials). Seven longer term trials of more intensive versus standard statin regimens (28 964 randomised patients and 1419 events) also showed no evidence of a reduction in the risk of atrial fibrillation (1.00, 0.90 to 1.12; P=0.99). Conclusions The suggested beneficial effect of statins on atrial fibrillation from published shorter term studies is not supported by a comprehensive review of published and unpublished evidence from larger scale trials.
    Full-text · Article · Mar 2011 · BMJ British medical journal
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    ABSTRACT: To estimate target and cardiac doses from breast cancer radiotherapy in Denmark and in the Stockholm and Umeå areas of Sweden during 1977-2001. 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. 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. 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.
    Full-text · Article · Mar 2011 · Radiotherapy and Oncology

Publication Stats

8k Citations
812.09 Total Impact Points

Institutions

  • 2013
    • University of Melbourne
      Melbourne, Victoria, Australia
  • 1998-2013
    • University of Oxford
      • Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU)
      Oxford, England, United Kingdom