Long-term follow-up is an important unmet need for the full analysis of new treatments for cancer. Earlier detection of cancer and more effective treatment have led to many more patients surviving ...for more than 5 and even 10 years, so that evaluating late recurrences and side-effects is an increasingly important issue. This is particularly relevant for oestrogen receptor-positive breast cancer, where the existence of late recurrences is well documented. However, survival for other cancers, notably prostate, colorectal and cervix cancer, has dramatically increased in recent years due to screening and better treatment of early lesions. Trials of preventive therapies have an even greater need for long follow-up. Here, we review these issues and suggest ways in which provision for long-term follow-up can be improved.
Background: The problems of adherence to energy restriction in humans are well known. Objective: To compare the feasibility and effectiveness of intermittent continuous energy (IER) with continuous ...energy restriction (CER) for weight loss, insulin sensitivity and other metabolic disease risk markers. Design: Randomized comparison of a 25% energy restriction as IER (approximately 2710 kJ/day for 2 days/week) or CER (approximately 6276 kJ/day for 7 days/week) in 107 overweight or obese (mean (+/-s.d.) body mass index 30.6 (+/-5.1) kg m-2) premenopausal women observed over a period of 6 months. Weight, anthropometry, biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, insulin-like growth factor (IGF)-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain-derived neurotrophic factor were assessed at baseline and after 1, 3 and 6 months. Results: Last observation carried forward analysis showed that IER and CER are equally effective for weight loss: mean (95% confidence interval ) weight change for IER was -6.4 (-7.9 to -4.8) kg vs -5.6 (-6.9 to -4.4) kg for CER (P-value for difference between groups=0.4). Both groups experienced comparable reductions in leptin, free androgen index, high-sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than with CER; difference between groups for fasting insulin was -1.2 (-1.4 to -1.0) micromoll-1 and for insulin resistance was -1.2 (-1.5 to -1.0) micromol-1 l-1 (both P=0.04). Conclusion: IER is as effective as CER with regard to weight loss, insulin sensitivity and other health biomarkers, and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk.
The quadrivalent human papillomavirus vaccine is effective in preventing infection and disease related to HPV types 6, 11, 16, and 18. This phase 3 trial involving 14,000 women reports the efficacy ...of a 9-valent vaccine that targets additional HPV types.
The human papillomavirus (HPV) causes premalignant and malignant lesions of the cervix,
1
,
2
vagina,
3
,
4
vulva,
4
,
5
anus,
4
,
6
penis,
7
and oropharynx,
8
as well as genital warts.
9
,
10
The recent development of prophylactic vaccines directed against the most relevant disease-causing HPV types has helped to prevent diseases related to HPV.
11
In clinical trials, the bivalent HPV viruslike particle vaccine against HPV types 16 and 18 was efficacious against related infection with these types and against cervical dysplasia,
12
and the quadrivalent HPV viruslike particle vaccine against types 6, 11, 16, and 18 was efficacious against related infection and against cervical, vaginal, . . .
Aspirin has been associated to a reduced risk of colorectal and possibly of a few other common cancers.
To provide an up-to-date quantification of this association, we conducted a meta-analysis of ...all observational studies on aspirin and 12 selected cancer sites published up to September 2011.
Regular aspirin is associated with a statistically significant reduced risk of colorectal cancer summary relative risk (RR) from random effects models = 0.73, 95% confidence interval (CI) 0.67–0.79, and of other digestive tract cancers (RR = 0.61, 95% CI = 0.50–0.76, for squamous cell esophageal cancer; RR = 0.64, 95% CI = 0.52–0.78, for esophageal and gastric cardia adenocarcinoma; and RR = 0.67, 95% CI = 0.54–0.83, for gastric cancer), with somewhat stronger reductions in risk in case–control than in cohort studies. Modest inverse associations were also observed for breast (RR = 0.90, 95% CI = 0.85–0.95) and prostate cancer (RR = 0.90, 95% CI = 0.85–0.96), while lung cancer was significantly reduced in case–control studies (0.73, 95% CI = 0.55–0.98) but not in cohort ones (RR = 0.98, 95% CI = 0.92–1.05). No meaningful overall associations were observed for cancers of the pancreas, endometrium, ovary, bladder, and kidney.
Observational studies indicate a beneficial role of aspirin on colorectal and other digestive tract cancers; modest risk reductions were also observed for breast and prostate cancer. Results are, however, heterogeneous across studies and dose–risk and duration–risk relationships are still unclear.
Objective To obtain large scale and generalisable data on the long term predictive value of cytology and human papillomavirus (HPV) testing for development of cervical intraepithelial neoplasia grade ...3 or cancer (CIN3+).Design Multinational cohort study with joint database analysis.Setting Seven primary HPV screening studies in six European countries.Participants 24 295 women attending cervical screening enrolled into HPV screening trials who had at least one cervical cytology or histopathology examination during follow-up.Main outcome measure Long term cumulative incidence of CIN3+.Results The cumulative incidence rate of CIN3+ after six years was considerably lower among women negative for HPV at baseline (0.27%, 95% confidence interval 0.12% to 0.45%) than among women with negative results on cytology (0.97%, 0.53% to 1.34%)). By comparison, the cumulative incidence rate for women with negative cytology results at the most commonly recommended screening interval in Europe (three years) was 0.51% (0.23% to 0.77%). The cumulative incidence rate among women with negative cytology results who were positive for HPV increased continuously over time, reaching 10% at six years, whereas the rate among women with positive cytology results who were negative for HPV remained below 3%.Conclusions A consistently low six year cumulative incidence rate of CIN3+ among women negative for HPV suggests that cervical screening strategies in which women are screened for HPV every six years are safe and effective.
Uncontrolled proliferation is a hallmark of cancer. In breast cancer, immunohistochemical assessment of the proportion of cells staining for the nuclear antigen Ki67 has become the most widely used ...method for comparing proliferation between tumor samples. Potential uses include prognosis, prediction of relative responsiveness or resistance to chemotherapy or endocrine therapy, estimation of residual risk in patients on standard therapy and as a dynamic biomarker of treatment efficacy in samples taken before, during, and after neoadjuvant therapy, particularly neoadjuvant endocrine therapy. Increasingly, Ki67 is measured in these scenarios for clinical research, including as a primary efficacy endpoint for clinical trials, and sometimes for clinical management. At present, the enormous variation in analytical practice markedly limits the value of Ki67 in each of these contexts. On March 12, 2010, an international panel of investigators with substantial expertise in the assessment of Ki67 and in the development of biomarker guidelines was convened in London by the cochairs of the Breast International Group and North American Breast Cancer Group Biomarker Working Party to consider evidence for potential applications. Comprehensive recommendations on preanalytical and analytical assessment, and interpretation and scoring of Ki67 were formulated based on current evidence. These recommendations are geared toward achieving a harmonized methodology, create greater between-laboratory and between-study comparability, and allow earlier valid applications of this marker in clinical practice.
Preventive therapy is a risk reduction option for women who have an increased risk of breast cancer. The effectiveness of preventive therapy to reduce breast cancer incidence depends on adequate ...levels of uptake and adherence to therapy. We aimed to systematically review articles reporting uptake and adherence to therapeutic agents to prevent breast cancer among women at increased risk, and identify the psychological, clinical and demographic factors affecting these outcomes.
Searches were carried out in PubMed, CINAHL, EMBASE and PsychInfo, yielding 3851 unique articles. Title, abstract and full text screening left 53 articles, and a further 4 studies were identified from reference lists, giving a total of 57. This review was prospectively registered with PROSPERO (CRD42014014957).
Twenty-four articles reporting 26 studies of uptake in 21 423 women were included in a meta-analysis. The pooled uptake estimate was 16.3% 95% confidence interval (CI) 13.6–19.0, with high heterogeneity (I2 = 98.9%, P < 0.001). Uptake was unaffected by study location or agent, but was significantly higher in trials 25.2% (95% CI 18.3–32.2) than in non-trial settings 8.7% (95% CI 6.8–10.9) (P < 0.001). Factors associated with higher uptake included having an abnormal biopsy, a physician recommendation, higher objective risk, fewer side-effect or trial concerns, and older age. Adherence (day-to-day use or persistence) over the first year was adequate. However, only one study reported a persistence of ≥80% by 5 years. Factors associated with lower adherence included allocation to tamoxifen (versus placebo or raloxifene), depression, smoking and older age. Risk of breast cancer was discussed in all qualitative studies.
Uptake of therapeutic agents for the prevention of breast cancer is low, and long-term persistence is often insufficient for women to experience the full preventive effect. Uptake is higher in trials, suggesting further work should focus on implementing preventive therapy within routine care.
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.
PDF
