Summary Background Statins lower high-sensitivity C-reactive protein (hsCRP) and cholesterol concentrations, and hypothesis generating analyses suggest that clinical outcomes improve in patients ...given statins who achieve hsCRP concentrations less than 2 mg/L in addition to LDL cholesterol less than 1·8 mmol/L (<70 mg/dL). However, the benefit of lowering both LDL cholesterol and hsCRP after the start of statin therapy is controversial. We prospectively tested this hypothesis. Methods In an analysis of 15 548 initially healthy men and women participating in the JUPITER trial (87% of full cohort), we prospectively assessed the effects of rosuvastatin 20 mg versus placebo on rates of non-fatal myocardial infarction, non-fatal stroke, admission for unstable angina, arterial revascularisation, or cardiovascular death (prespecified endpoints) during a maximum follow-up of 5 years (median 1·9 years), according to on-treatment concentrations of LDL cholesterol (≥1·8 mmol/L or <1·8 mmol/L) and hsCRP (≥2 mg/L or <2 mg/L). We included all events occurring after randomisation. This trial is registered with ClinicalTrials.gov , number NCT00239681. Findings Compared with placebo, participants allocated to rosuvastatin who achieved LDL cholesterol less than 1·8 mmol/L had a 55% reduction in vascular events (event rate 1·11 vs 0·51 per 100 person-years; hazard ratio HR 0·45, 95% CI 0·34–0·60, p<0·0001), and those achieving hsCRP less than 2 mg/L a 62% reduction (event rate 0·42 per 100 person-years; HR 0·38, 95% CI 0·26–0·56, p<0·0001). Although LDL cholesterol and hsCRP reductions were only weakly correlated in individual patients ( r values <0·15), we recorded a 65% reduction in vascular events in participants allocated to rosuvastatin who achieved both LDL cholesterol less than 1·8 mmol/L and hsCRP less than 2 mg/L (event rate 0·38 per 100 person-years; adjusted HR 0·35, 95% CI 0·23–0·54), versus a 33% reduction in those who achieved one or neither target (event rate 0·74 per 100 person-years; HR 0·67, 95% CI 0·52–0·87) (p across treatment groups <0·0001). In participants who achieved LDL cholesterol less than 1·8 mmol/L and hsCRP less than 1 mg/L, we noted a 79% reduction (event rate 0·24 per 100 person-years; HR 0·21, 95% CI 0·09–0·52). Achieved hsCRP concentrations were predictive of event rates irrespective of the lipid endpoint used, including the apolipoprotein B to apolipoprotein AI ratio. Interpretation For people choosing to start pharmacological prophylaxis, reduction in both LDL cholesterol and hsCRP are indicators of successful treatment with rosuvastatin. Funding AstraZeneca.
Summary Background Inter-individual differences in biological ageing could affect susceptibility to coronary heart disease. Our aim was to determine whether mean leucocyte telomere length is a ...predictor of the development of coronary heart disease. Methods We compared telomere lengths at recruitment in 484 individuals in the West of Scotland Primary Prevention Study (WOSCOPS) who went on to develop coronary heart disease events with those from 1058 matched controls who remained event free. We also investigated whether there was any association between telomere length and observed clinical benefit of statin treatment in WOSCOPS. Findings Mean telomere length decreased with age by 9% per decade (95% CI 3·6–14·1; p=0·001) in controls; much the same trend was seen in cases (−5·9% per decade, −3·1 to 14·1; p=0·1902). Individuals in the middle and the lowest tertiles of telomere length were more at risk of developing a coronary heart disease event than were individuals in the highest tertile (odds ratio OR for coronary heart disease: 1·51, 95% CI 1·15–1·98; p=0·0029 in the middle tertile; 1·44, 1·10–1·90, p=0·0090 in the lowest). In placebo-treated patients, the risk of coronary heart disease was almost double in those in the lower two tertiles of telomere length compared with those in the highest tertile (1·93, 1·33–2·80, p=0·0005 in the middle tertile; 1·94, 1·33–2·84, p=0·0006 in the lowest). By contrast, in patients treated with pravastatin, the increased risk with shorter telomeres was substantially attenuated (1·12, 0·75–1·69, p=0·5755 in the middle tertile; 1·02, 0·68–1·52, p=0·9380 in the lowest). Interpretation Mean leucocyte telomere length is a predictor of future coronary heart disease events in middle-aged, high-risk men and could identify individuals who would benefit most from statin treatment. Our findings lend support to the hypothesis that differences in biological ageing might contribute to the risk—and variability in age of onset—of coronary heart disease.
Summary Background Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases (N2) have shown the feasibility of resection ...after concurrent chemotherapy and radiotherapy with promising rates of survival. We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection. Methods Patients with stage T1-3pN2M0 non-small-cell lung cancer were randomly assigned in a 1:1 ratio to concurrent induction chemotherapy (two cycles of cisplatin 50 mg/m2 on days 1, 8, 29, and 36 and etoposide 50 mg/m2 on days 1–5 and 29–33) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00002550. Findings 202 patients (median age 59 years, range 31–77) were assigned to group 1 and 194 (61 years, 32–78) to group 2. Median OS was 23·6 months (IQR 9·0–not reached) in group 1 versus 22·2 months (9·4–52·7) in group 2 (hazard ratio HR 0·87 0·70–1·10; p=0·24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0·63 0·36–1·10; p=0·10). With N0 status at thoracotomy, the median OS was 34·4 months (IQR 15·7–not reached; 19 point estimate 41% patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12·8 months (5·3–42·2) vs 10·5 months (4·8–20·6), HR 0·77 0·62–0·96; p=0·017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 38% and 20 10%, respectively) and group 2 (80 41% and 44 23%, respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy. Interpretation Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) non-small-cell lung cancer. Funding National Cancer Institute, Canadian Cancer Society, and National Cancer Institute of Canada.
Summary Background In the non-curative setting, the sequence in which anticancer agents are used, singly or in combination, may be important if patients are to receive the maximum period of disease ...control with the minimum of adverse effects. We compared sequential and combination chemotherapy strategies in patients with unpretreated advanced or metastatic colorectal cancer, who were regarded as not potentially curable irrespective of response. Methods We studied patients with advanced colorectal cancer, starting treatment with non-curative intent. 2135 unpretreated patients were randomly assigned to three treatment strategies in the ratio 1:1:1. Strategy A (control group) was single-agent fluorouracil (given with levofolinate over 48 h every 2 weeks) until failure, then single-agent irinotecan. Strategy B was fluorouracil until failure, then combination chemotherapy. Strategy C was combination chemotherapy from the outset. Within strategies B and C, patients were randomly assigned to receive, as the combination regimen, fluorouracil plus irinotecan (groups B-ir and C-ir) or fluorouracil plus oxaliplatin (groups B-ox and C-ox). The primary endpoint was overall survival, analysed by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 79877428. Results Median survival of patients allocated to control strategy A was 13·9 months. Median survival of each of the other groups was longer (B-ir 15·0, B-ox 15·2, C-ir 16·7, and C-ox 15·4 months). However, log-rank comparison of each group against control showed that only C-ir—the first-line combination strategy including irinotecan—satisfied the statistical test for superiority (p=0·01). Overall comparison of strategy B with strategy C was within the predetermined non-inferiority boundary of HR=1·18 or less (HR=1·06, 90% CI 0·97–1·17). Interpretation Our data challenge the assumption that, in this non-curative setting, maximum tolerable treatment must necessarily be used first-line. The staged approach of initial single-agent treatment upgraded to combination when required is not worse than first-line combination, and is an alternative option for discussion with patients.
Summary Background Treatment of breast cancer with aromatase inhibitors is associated with damage to bones. NCIC CTG MA.27 was an open-label, phase 3, randomised controlled trial in which women with ...breast cancer were assigned to one of two adjuvant oral aromatase inhibitors—exemestane or anastrozole. We postulated that exemestane—a mildly androgenic steroid—might have a less detrimental effect on bone than non-steroidal anastrozole. In this companion study to MA.27, we compared changes in bone mineral density (BMD) in the lumbar spine and total hip between patients treated with exemestane and patients treated with anastrozole. Methods In MA.27, postmenopausal women with early stage hormone (oestrogen) receptor-positive invasive breast cancer were randomly assigned to exemestane 25 mg versus anastrozole 1 mg, daily. MA.27B recruited two groups of women from MA.27: those with BMD T-scores of −2·0 or more (up to 2 SDs below sex-matched, young adult mean) and those with at least one T-score (hip or spine) less than −2·0. Both groups received vitamin D and calcium; those with baseline T-scores of less than −2·0 also received bisphosphonates. The primary endpoints were percent change of BMD at 2 years in lumbar spine and total hip for both groups. We analysed patients according to which aromatase inhibitor and T-score groups they were allocated to but BMD assessments ceased if patients deviated from protocol. This study is registered with ClinicalTrials.gov , NCT00354302. Findings Between April 24, 2006, and May 30, 2008, 300 patients with baseline T-scores of −2·0 or more were accrued (147 allocated exemestane, 153 anastrozole); and 197 patients with baseline T-scores of less than −2·0 (101 exemestane, 96 anastrozole). For patients with T-scores greater than −2·0 at baseline, mean change of bone mineral density in the spine at 2 years did not differ significantly between patients taking exemestane and patients taking anastrozole (−0·92%, 95% CI −2·35 to 0·50 vs −2·39%, 95% CI −3·77 to −1·01; p=0·08). Respective mean loss in the hip was −1·93% (95% CI −2·93 to −0·93) versus −2·71% (95% CI −4·32 to −1·11; p=0·10). Likewise for those who started with T-scores of less than −2·0, mean change of spine bone mineral density at 2 years did not differ significantly between the exemestane and anastrozole treatment groups (2·11%, 95% CI −0·84 to 5·06 vs 3·72%, 95% CI 1·54 to 5·89; p=0·26), nor did hip bone mineral density (2·09%, 95% CI −1·45 to 5·63 vs 0·0%, 95% CI −3·67 to 3·66; p=0·28). Patients with baseline T-score of −2·0 or more taking exemestane had two fragility fractures and two other fractures, those taking anastrozole had three fragility fractures and five other fractures. For patients who had baseline T-scores of less than −2·0 taking exemestane, one had a fragility fracture and four had other fractures, whereas those taking anastrozole had five fragility fractures and one other fracture. Interpretation Our results demonstrate that adjuvant treatment with aromatase inhibitors can be considered for breast cancer patients who have T-scores less than −2·0. Funding Canadian Cancer Society Research Institute, Pfizer, Canadian Institutes of Health Research.
Non-small-cell lung cancer Goldstraw, Peter, Prof; Ball, David, Prof; Jett, James R, MD ...
The Lancet (British edition),
11/2011, Letnik:
378, Številka:
9804
Journal Article
Recenzirano
Summary In the decade since the last Lancet Seminar on lung cancer there have been advances in many aspects of the classification, diagnosis, and treatment of non-small-cell lung cancer (NSCLC). An ...international panel of experts has been brought together to focus on changes in the epidemiology and pathological classification of NSCLC, the role of CT screening and other techniques that could allow earlier diagnosis and more effective treatment of the disease, and the recently introduced seventh edition of the TNM classification and its relation to other prognostic factors such as biological markers. We also describe advances in treatment that have seen the introduction of a new generation of chemotherapy agents, a proven advantage to adjuvant chemotherapy after complete resection for specific stage groups, new techniques for the planning and administration of radiotherapy, and new surgical approaches to assess and reduce the risks of surgical treatment.
Summary Background The 21-gene recurrence score assay is prognostic for women with node-negative, oestrogen-receptor-positive breast cancer treated with tamoxifen. A low recurrence score predicts ...little benefit of chemotherapy. For node-positive breast cancer, we investigated whether the recurrence score was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher risks of recurrence. Methods The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumour banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, we assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes. Findings There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0·006; hazard ratio HR 2·64, 95% CI 1·33–5·27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score <18; log-rank p=0·97; HR 1·02, 0·54–1·93), but an improvement in disease-free survival for those with a high recurrence score (score ≥31; log-rank p=0·033; HR 0·59, 0·35–1·01), after adjustment for number of positive nodes. The recurrence score by treatment interaction was significant in the first 5 years (p=0·029), with no additional prediction beyond 5 years (p=0·58), although the cumulative benefit remained at 10 years. Results were similar for overall survival and breast-cancer-specific survival. Interpretation The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence score identifies women who might not benefit from anthracycline-based chemotherapy, despite positive nodes. Funding National Cancer Institute and Genomic Health.
Summary Background Clinical use of criteria for metabolic syndrome to simultaneously predict risk of cardiovascular disease and diabetes remains uncertain. We investigated to what extent metabolic ...syndrome and its individual components were related to risk for these two diseases in elderly populations. Methods We related metabolic syndrome (defined on the basis of criteria from the Third Report of the National Cholesterol Education Program) and its five individual components to the risk of events of incident cardiovascular disease and type 2 diabetes in 4812 non-diabetic individuals aged 70–82 years from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). We corroborated these data in a second prospective study (the British Regional Heart Study BRHS) of 2737 non-diabetic men aged 60–79 years. Findings In PROSPER, 772 cases of incident cardiovascular disease and 287 of diabetes occurred over 3·2 years. Metabolic syndrome was not associated with increased risk of cardiovascular disease in those without baseline disease (hazard ratio 1·07 95% CI 0·86–1·32) but was associated with increased risk of diabetes (4·41 3·33–5·84) as was each of its components, particularly fasting glucose (18·4 13·9–24·5). Results were similar in participants with existing cardiovascular disease. In BRHS, 440 cases of incident cardiovascular disease and 105 of diabetes occurred over 7 years. Metabolic syndrome was modestly associated with incident cardiovascular disease (relative risk 1·27 1·04–1·56) despite strong association with diabetes (7·47 4·90–11·46). In both studies, body-mass index or waist circumference, triglyceride, and glucose cutoff points were not associated with risk of cardiovascular disease, but all five components were associated with risk of new-onset diabetes. Interpretation Metabolic syndrome and its components are associated with type 2 diabetes but have weak or no association with vascular risk in elderly populations, suggesting that attempts to define criteria that simultaneously predict risk for both cardiovascular disease and diabetes are unhelpful. Clinical focus should remain on establishing optimum risk algorithms for each disease. Funding Diabetes UK and British Heart Foundation.
PDF
