Hongchao Pan

Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials.

Summary Background Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences. Methods 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. Findings 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. Interpretation 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. Funding Cancer Research UK; British Heart Foundation; UK Medical Research Council.BACKGROUND Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences. METHODS 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. FINDINGS 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. INTERPRETATION 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. FUNDING Cancer Research UK; British Heart Foundation; UK Medical Research Council.

Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial

Summary Background For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. Methods In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. Findings Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79–1·02] during years 5–9 and 0·75 [0·62–0·90] in later years; breast cancer mortality RR 0·97 [0·79–1·18] during years 5–9 and 0·71 [0·58–0·88] in later years). The cumulative risk of recurrence during years 5–14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5–14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12 894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89–1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13–3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83–1·36), ischaemic heart disease 0·76 (0·60–0·95, p=0·02), and endometrial cancer 1·74 (1·30–2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5–14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). Interpretation For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. Funding Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.

Indications for early aspirin use in acute ischemic stroke : A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups.

BACKGROUND AND PURPOSE Long-term daily aspirin is of benefit in the years after ischemic stroke, and 2 large randomized trials (the Chinese Acute Stroke Trial [CAST] and the International Stroke Trial [IST]), with 20 000 patients in each, have shown that starting daily aspirin promptly in patients with suspected acute ischemic stroke also reduces the immediate risk of further stroke or death in hospital and the overall risk of death or dependency. However, some uncertainty remains about the effects of early aspirin in particular categories of patient with acute stroke. METHODS To assess the balance of benefits and risks of aspirin in particular categories of patient with acute stroke (eg, the elderly, those without a CT scan, or those with atrial fibrillation), a prospectively planned meta-analysis is presented of the data from 40 000 individual patients from both trials on events that occurred in the hospital during the scheduled treatment period (4 weeks in CAST, 2 weeks in IST), with 10 characteristics used to define 28 subgroups. This represents 99% of the worldwide evidence from randomized trials. RESULTS There was a highly significant reduction of 7 per 1000 (SD 1) in recurrent ischemic stroke (320 [1.6%] aspirin versus 457 [2. 3%] control, 2P<0.000001) and a less clearly significant reduction of 4 (SD 2) per 1000 in death without further stroke (5.0% versus 5. 4%, 2P=0.05). Against these benefits, there was an increase of 2 (SD 1) per 1000 in hemorrhagic stroke or hemorrhagic transformation of the original infarct (1.0% versus 0.8%, 2P=0.07) and no apparent effect on further stroke of unknown cause (0.9% versus 0.9%). In total, therefore, there was a net decrease of 9 (SD 3) per 1000 in the overall risk of further stroke or death in hospital (8.2% versus 9.1%, 2P=0.001). For the reduction of one third in recurrent ischemic stroke, subgroup-specific analyses found no significant heterogeneity of the proportional benefit of aspirin (chi(2)(18)=20. 9, NS), even though the overall treatment effect (chi(2)(1)=24.8, 2P<0.000001) was sufficiently large for such subgroup analyses to be statistically informative. The absolute risk among control patients was similar in all 28 subgroups, so the absolute reduction of approximately 7 per 1000 in recurrent ischemic stroke does not differ substantially with respect to age, sex, level of consciousness, atrial fibrillation, CT findings, blood pressure, stroke subtype, or concomitant heparin use. There was no good evidence that the apparent decrease of approximately 4 per 1000 in death without further stroke was reversed in any subgroup or that in any subgroup the increase in hemorrhagic stroke was much larger than the overall average of approximately 2 per 1000. Finally, there was no significant heterogeneity between the reductions in the composite outcome of any further stroke or death (chi(2)(18)=16.5, NS). Among the 9000 patients (22%) randomized without a prior CT scan, aspirin appeared to be of net benefit with no unusual excess of hemorrhagic stroke; moreover, even among the 800 (2%) who had inadvertently been randomized after a hemorrhagic stroke, there was no evidence of net hazard (further stroke or death, 63 aspirin versus 67 control). CONCLUSIONS Early aspirin is of benefit for a wide range of patients, and its prompt use should be routinely considered for all patients with suspected acute ischemic stroke, mainly to reduce the risk of early recurrence.

10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): a multicentre randomised trial.

Summary Background If carotid artery narrowing remains asymptomatic (ie, has caused no recent stroke or other neurological symptoms), successful carotid endarterectomy (CEA) reduces stroke incidence for some years. We assessed the long-term effects of successful CEA. Methods Between 1993 and 2003, 3120 asymptomatic patients from 126 centres in 30 countries were allocated equally, by blinded minimised randomisation, to immediate CEA (median delay 1 month, IQR 0·3–2·5) or to indefinite deferral of any carotid procedure, and were followed up until death or for a median among survivors of 9 years (IQR 6–11). The primary outcomes were perioperative mortality and morbidity (death or stroke within 30 days) and non-perioperative stroke. Kaplan-Meier percentages and logrank p values are from intention-to-treat analyses. This study is registered, number ISRCTN26156392. Findings 1560 patients were allocated immediate CEA versus 1560 allocated deferral of any carotid procedure. The proportions operated on while still asymptomatic were 89·7% versus 4·8% at 1 year (and 92·1% vs 16·5% at 5 years). Perioperative risk of stroke or death within 30 days was 3·0% (95% CI 2·4–3·9; 26 non-disabling strokes plus 34 disabling or fatal perioperative events in 1979 CEAs). Excluding perioperative events and non-stroke mortality, stroke risks (immediate vs deferred CEA) were 4·1% versus 10·0% at 5 years (gain 5·9%, 95% CI 4·0–7·8) and 10·8% versus 16·9% at 10 years (gain 6·1%, 2·7–9·4); ratio of stroke incidence rates 0·54, 95% CI 0·43–0·68, p<0·0001. 62 versus 104 had a disabling or fatal stroke, and 37 versus 84 others had a non-disabling stroke. Combining perioperative events and strokes, net risks were 6·9% versus 10·9% at 5 years (gain 4·1%, 2·0–6·2) and 13·4% versus 17·9% at 10 years (gain 4·6%, 1·2–7·9). Medication was similar in both groups; throughout the study, most were on antithrombotic and antihypertensive therapy. Net benefits were significant both for those on lipid-lowering therapy and for those not, and both for men and for women up to 75 years of age at entry (although not for older patients). Interpretation Successful CEA for asymptomatic patients younger than 75 years of age reduces 10-year stroke risks. Half this reduction is in disabling or fatal strokes. Net benefit in future patients will depend on their risks from unoperated carotid lesions (which will be reduced by medication), on future surgical risks (which might differ from those in trials), and on whether life expectancy exceeds 10 years. Funding UK Medical Research Council, BUPA Foundation, Stroke Association.

Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials

BACKGROUND The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain. METHODS We undertook meta-analyses of individual data on 31,920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials of 5 years of aromatase inhibitor versus 5 years of tamoxifen; of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5; and of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen. Primary outcomes were any recurrence of breast cancer, breast cancer mortality, death without recurrence, and all-cause mortality. Intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded aromatase inhibitor versus tamoxifen first-event rate ratios (RRs). FINDINGS In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·64, 95% CI 0·52-0·78) and 2-4 (RR 0·80, 0·68-0·93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12·1% vs 14·2%; RR 0·85, 0·75-0·96; 2p=0·009). In the comparison of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·74, 0·62-0·89) but not while both groups received aromatase inhibitors during years 2-4, or thereafter; overall in these trials, there were fewer recurrences with 5 years of aromatase inhibitors than with tamoxifen then aromatase inhibitors (RR 0·90, 0·81-0·99; 2p=0·045), though the breast cancer mortality reduction was not significant (RR 0·89, 0·78-1·03; 2p=0·11). In the comparison of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 2-4 (RR 0·56, 0·46-0·67) but not subsequently, and 10-year breast cancer mortality was lower with switching to aromatase inhibitors than with remaining on tamoxifen (8·7% vs 10·1%; 2p=0·015). Aggregating all three types of comparison, recurrence RRs favoured aromatase inhibitors during periods when treatments differed (RR 0·70, 0·64-0·77), but not significantly thereafter (RR 0·93, 0·86-1·01; 2p=0·08). Breast cancer mortality was reduced both while treatments differed (RR 0·79, 0·67-0·92), and subsequently (RR 0·89, 0·81-0·99), and for all periods combined (RR 0·86, 0·80-0·94; 2p=0·0005). All-cause mortality was also reduced (RR 0·88, 0·82-0·94; 2p=0·0003). RRs differed little by age, body-mass index, stage, grade, progesterone receptor status, or HER2 status. There were fewer endometrial cancers with aromatase inhibitors than tamoxifen (10-year incidence 0·4% vs 1·2%; RR 0·33, 0·21-0·51) but more bone fractures (5-year risk 8·2% vs 5·5%; RR 1·42, 1·28-1·57); non-breast-cancer mortality was similar. INTERPRETATION Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments differ, but not thereafter. 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment. FUNDING Cancer Research UK, Medical Research Council.

Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

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.

Emerging tobacco hazards in China: 2. Early mortality results from a prospective study

Objective: To monitor the evolving epidemic of mortality from tobacco in China following the large increase in male cigarette use in recent decades. Design: Prospective study of smoking and mortality starting with 224 500 interviewees who should eventually be followed for some decades. Setting: 45 nationally representative small urban or rural areas distributed across China. Subjects: Male population aged 40 or over in 1991, of whom about 80% were interviewed about smoking, drinking, and medical history. Main outcome measure: Cause specific mortality, initially to 1995 but later to continue, with smoker versus non-smoker risk ratios standardised for area, age, and use of alcohol. Results: 74% were smokers (73% current, only 1% former), but few of this generation would have smoked substantial numbers of cigarettes since early adult life. Overall mortality is increased among smokers (risk ratio 1.19; 95% confidence interval 1.13 to 1.25, P<0.0001). Almost all the increased mortality involved neoplastic, respiratory, or vascular disease. The overall risk ratios currently associated with smoking are less extreme in rural areas (1.26, 1.12, or 1.02 respectively for smokers who started before age 20, at 20-24, or at older ages) than in urban areas (1.73, 1.40, or 1.16 respectively). Conclusion: This prospective study and the accompanying retrospective study show that by 1990 smoking was already causing about 12% of Chinese male mortality in middle age. This proportion is predicted to rise to about 33% by 2030. Long term continuation of the prospective study (with periodic resurveys) can monitor the evolution of this epidemic.

Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death

Summary Background 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. Methods 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. Findings 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. Interpretation 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. Funding Cancer Research UK, British Heart Foundation, and UK Medical Research Council.Breast-conserving surgery can excise all detected macroscopic tumor tissue in women with early-stage breast cancer. However, the presence of microscopic tumor foci in the conserved breast of these women, if untreated, may lead to locoregional recurrence and/or life-threatening distant recurrence. Radiotherapy in the conserved breast after surgery may reduce rates of recurrence and breast cancer death more among some groups of women than in others. This meta-analysis assessed the extent to which the absolute reduction by radiotherapy in 10-year risk of first recurrence differs among women with different prognostic and other characteristics and relates the absolute reduction in the 15-year risk of breast cancer death to the absolute reduction in the 10-year recurrence risk. 92 Obstetrical and Gynecological Survey

Risk of Stroke From New Carotid Artery Occlusion in the Asymptomatic Carotid Surgery Trial-1

Background and Purpose— In the Asymptomatic Carotid Surgery Trial-1 (ACST-1), 3120 patients with tight asymptomatic carotid stenosis were randomly assigned to medical treatment alone or to carotid endarterectomy and appropriate medication. Successful carotid endarterectomy significantly reduced 10-year stroke risk in younger patients. This study was undertaken to determine the risk of new occlusion and stroke during trial follow-up. Methods— Patients with contralateral occlusion at trial entry (n=276) or incomplete duplex follow-up (n=137) were excluded. Risk of occlusion and stroke in patients with occlusion was estimated by Kaplan–Meier analysis. Cox proportional hazard regression models were used to determine risk factors for developing new occlusion and stroke. Results— Median follow-up in 2707 patients was 80.0 months (interquartile range, 52.0–115.0). New occlusions occurred in 197 patients (1.1% per annum) but were more likely to occur in arteries with tight stenosis and in unoperated patients. Overall risk of stroke was 7.6% (95% confidence interval [CI], 6.6–8.7) and 15.5% (95% CI, 13.6–17.4) at 5 and 10 years, respectively; for patients with new occlusion, this significantly increased to 17.0% (95% CI, 11.6–22.4) and 20.8% (95% CI, 14.1–26.2), respectively (P<0.001). Stroke was significantly more likely to occur in patients developing occlusion (hazard ratio, 1.78; 95% CI, 1.26–2.51) irrespective of allocated treatment. Conclusions— New occlusions were uncommon after carotid endarterectomy in ACST-1. During long-term follow-up, occlusion and stroke were commoner among patients with ≥70% stenosis, most of whom had not undergone carotid endarterectomy. Occlusion was an independent prognostic risk factor for occurrence of stroke.

Ten-year risk of stroke in patients with previous cerebral infarction and the impact of carotid surgery in the Asymptomatic Carotid Surgery Trial

Background Silent brain infarcts are common in patients at increased risk of stroke and are associated with a poor prognosis. In patients with asymptomatic carotid stenosis, similar adverse associations were claimed, but the impact of previous infarction or symptoms on the beneficial effects of carotid endarterectomy is not clear. Our aim was to evaluate the impact of prior cerebral infarction in patients enrolled in the Asymptomatic Carotid Surgery Trial, a large trial with 10-year follow-up in which participants whose carotid stenosis had not caused symptoms for at least six months were randomly allocated either immediate or deferred carotid endarterectomy. Methods The first Asymptomatic Carotid Surgery Trial included 3120 patients. Of these, 2333 patients with baseline brain imaging were identified and divided into two groups irrespective of treatment assignment, 1331 with evidence of previous cerebral infarction, defined as a history of ischemic stroke or transient ischemic attack > 6 months prior to randomization or radiological evidence of an asymptomatic infarct (group 1) and 1002 with normal imaging and no prior stroke or transient ischemic attack (group 2). Stroke and vascular deaths were compared during follow-up, and the impact of carotid endarterectomy was observed in both groups. Results Baseline characteristics of patients with and without baseline brain imaging were broadly similar. Of those included in the present report, male gender and hypertension were more common in group 1, while mean ipsilateral stenosis was slightly greater in group 2. At 10 years follow-up, stroke was more common among participants with cerebral infarction before randomization (absolute risk increase 5.8% (1.8–9.8), p = 0.004), and the risk of stroke and vascular death was also higher in this group (absolute risk increase 6.9% (1.9–12.0), p = 0.007). On multivariate analysis, prior cerebral infarction was associated with a greater risk of stroke (hazard ratio = 1.51, 95% confidence interval: 1.17–1.95, p = 0.002) and of stroke or other vascular death (hazard ratio = 1.30, 95% confidence interval: 1.11–1.52, p = 0.001). At 10 years, greater absolute benefits from immediate carotid endarterectomy were seen in those patients with prior cerebral infarction (6.7% strokes immediate carotid endarterectomy vs. 14.7% delayed carotid endarterectomy; hazard ratio 0.47 (0.34–0.65), p = 0.003), compared to those lower risk patients without prior cerebral infarction (6.0% vs. 9.9%, respectively; hazard ratio 0.61 (0.39–0.94), p = 0.005), though it must be emphasized that the first Asymptomatic Carotid Surgery Trial was not designed to test this retrospective and non-randomized comparison. Conclusions Asymptomatic carotid stenosis patients with prior cerebral infarction have a higher stroke risk during long-term follow-up than those without prior cerebral infarction. Evidence of prior ischemic events might help identify patients in whom carotid intervention is particularly beneficial.