An approach to estimating prognosis using fractional polynomials in metastatic renal carcinoma

We present a prognostic model for metastatic renal cell carcinoma based on fractional polynomials. We retrospectively analysed 425 metastatic renal cell carcinoma patients treated with subcutaneous recombinant cytokine-based home therapies in consecutive trials. In our approach, we categorised a continuous prognostic index produced by the multivariable fractional polynomial (MFP) algorithm, using a strategy in which continuous predictors are kept continuous. The MFP algorithm selected five prognostic factors as significant at the 5% level in a multivariable model: lymph node metastases, liver metastases, bone metastases, age, C-reactive protein and neutrophils. The MFP model allowed us to divide patients into four risk groups achieving median overall survivals of 38 months (low risk), 23 months (low intermediate risk), 15 months (high intermediate risk) and 5.6 months (high risk). Our approach, based on categorising a continuous prognostic index produced by the MFP algorithm, allowed more flexibility in the determination of risk groups than traditional approaches

Efficacy of RTS,S malaria vaccines: individual-participant pooled analysis of phase 2 data.

BACKGROUND: The efficacy of RTS,S/AS01 as a vaccine for malaria is being tested in a phase 3 clinical trial. Early results show significant, albeit partial, protection against clinical malaria and severe malaria. To ascertain variations in vaccine efficacy according to covariates such as transmission intensity, choice of adjuvant, age at vaccination, and bednet use, we did an individual-participant pooled analysis of phase 2 clinical data. METHODS: We analysed data from 11 different sites in Africa, including 4453 participants. We measured heterogeneity in vaccine efficacy by estimating the interactions between covariates and vaccination in pooled multivariable Cox regression and Poisson regression analyses. Endpoints for measurement of vaccine efficacy were infection, clinical malaria, severe malaria, and death. We defined transmission intensity levels according to the estimated local parasite prevalence in children aged 2-10 years (PrP₂₋₁₀), ranging from 5% to 80%. Choice of adjuvant was either AS01 or AS02. FINDINGS: Vaccine efficacy against all episodes of clinical malaria varied by transmission intensity (p=0·001). At low transmission (PrP₂₋₁₀ 10%) vaccine efficacy was 60% (95% CI 54 to 67), at moderate transmission (PrP₂₋₁₀ 20%) it was 41% (21 to 57), and at high transmission (PrP₂₋₁₀ 70%) the efficacy was 4% (-10 to 22). Vaccine efficacy also varied by adjuvant choice (p<0·0001)--eg, at low transmission (PrP₂₋₁₀ 10%), efficacy varied from 60% (95% CI 54 to 67) for AS01 to 47% (14 to 75) for AS02. Variations in efficacy by age at vaccination were of borderline significance (p=0·038), and bednet use and sex were not significant covariates. Vaccine efficacy (pooled across adjuvant choice and transmission intensity) varied significantly (p<0·0001) according to time since vaccination, from 36% efficacy (95% CI 24 to 45) at time of vaccination to 0% (-38 to 38) after 3 years. INTERPRETATION: Vaccine efficacy against clinical disease was of limited duration and was not detectable 3 years after vaccination. Furthermore, efficacy fell with increasing transmission intensity. Outcomes after vaccination cannot be gauged accurately on the basis of one pooled efficacy figure. However, predictions of public-health outcomes of vaccination will need to take account of variations in efficacy by transmission intensity and by time since vaccination. FUNDING: Medical Research Council (UK); Bill & Melinda Gates Foundation Vaccine Modelling Initiative; Wellcome Trust

Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL

ADMIRE was a multi-center, randomized-controlled, open, phase IIB superiority trial in previously untreated Chronic Lymphocytic Leukemia (CLL). Conventional frontline therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). Initial evidence from non-randomized Phase II trials suggested that the addition of mitoxantrone to FCR (FCM-R) improved remission rates. 215 patients were recruited to assess the primary endpoint of complete remission (CR) rates according to IWCLL criteria. Secondary endpoints were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity and safety. At final analysis, CR rates were 69.8% FCR vs 69.3% FCM-R [adjusted odds ratio (OR): 0.97; 95%CI: (0.53-1.79), P=0.932]. MRD-negativity rates were 59.3% FCR vs 50.5% FCM-R [adjusted OR: 0.70; 95% CI: (0.39-1.26), P=0.231]. During treatment, 60.0% (n=129) of participants received G-CSF as secondary prophylaxis for neutropenia, a lower proportion on FCR compared with FCM-R (56.1 vs 63.9%). The toxicity of both regimens was acceptable. There are no significant differences between the treatment groups for PFS and OS. The trial demonstrated that the addition of mitoxantrone to FCR did not increase the depth of response. Oral FCR was well tolerated and resulted in impressive responses in terms of CR rates and MRD negativity compared to historical series with intravenous chemotherapy

Hematocrit and the Risk of Recurrent Venous Thrombosis: A Prospective Cohort Study

BACKGROUND: Venous thromboembolism (VTE) is a multicausal disease which recurs. Hematocrit is associated with a thrombotic risk. We aimed to investigate if hematocrit is associated with the recurrence risk. METHODS: Patients with a first VTE were followed after anticoagulation. Patients with VTE provoked by a transient risk factor, natural inhibitor deficiency, lupus anticoagulant, homozygous or double heterozygous defects, cancer, or long-term antithrombotic treatment were excluded. The study endpoint was recurrent VTE. RESULTS: 150 (23%) of 653 patients had recurrence. Only high hematocrit was significantly associated with recurrence risk [hazard ratio (HR) for 1% hematocrit increase with the third tertile 1.08; 95% CI 1.01-1.15]. No or only a weak association for hematocrits within the first and second tertile was seen (HR 1.03; 95% CI 0.97-1.09, and 1.07; 95% CI 1.00-1.13). Hematocrit was associated with recurrence risk only among women. After five years, the probability of recurrence was 9.9% (95% CI 3.7%-15.7%), 15.6% (95% CI 9.7%-21.2%) and 25.5% (95% CI 15.1%-34.6%) in women, and was 29.2% (95% CI 21.1%-36.5%), 30.1% (95% CI 24.1%-35.7%) and 30.8% (95% CI 22.0%-38.7%) in men for hematocrits in the first, second and third tertile, respectively. Men had a higher recurrence risk (1.9; 95% CI 1.1-2.7; p = 0.03), which dropped by 23.5% after adjustment for hematocrit. Hematocrit was not a significant mediator of the sex-difference in recurrence risk (p = 0.223). CONCLUSIONS: High hematocrit is associated with the recurrence only in women. The different recurrence risk between men and women is possibly partly explained by hematocrit

Communicating effectiveness of intervention for chronic diseases: what single format can replace comprehensive information?

<p>Abstract</p> <p>Background</p> <p>There is uncertainty about how GPs should convey information about treatment effectiveness to their patients in the context of cardiovascular disease. Hence we study the concordance of decisions based on one of four single information formats for treatment effectiveness with subsequent decisions based on all four formats combined with a pictorial representation.</p> <p>Methods</p> <p>A randomized study comprising 1,169 subjects aged 40–59 in Odense, Denmark. Subjects were randomized to receive information in terms of absolute risk reduction (ARR), relative risk reduction (RRR), number needed to treat (NNT), or prolongation of life (POL) without heart attack, and were asked whether they would consent to treatment. Subsequently the same information was conveyed with all four formats jointly accompanied by a pictorial presentation of treatment effectiveness. Again, subjects should consider consent to treatment.</p> <p>Results</p> <p>After being informed about all four formats, 52%–79% of the respondents consented to treatment, depending on level of effectiveness and initial information format. Overall, ARR gave highest concordance, 94% (95% confidence interval (91%; 97%)) between initial and final decision, but ARR was not statistically superior to the other formats.</p> <p>Conclusion</p> <p>Decisions based on ARR had the best concordance with decisions based on all four formats and pictorial representation, but the difference in concordance between the four formats was small, and it is unclear whether respondents fully understood the information they received.</p

Metastatic renal carcinoma comprehensive prognostic system

The purpose of the study was to identify a comprehensive prognostic system of pretreatment clinical parameters in 425 patients (pts) with metastatic renal-cell carcinoma treated with different subcutaneous (s.c.) recombinant cytokine-based home therapies in consecutive trials. Treatment consisted of (A) s.c. interferon-α2a (INF-α), s.c. interleukin-2 (IL-2) (n=102 pts), (B) s.c. IFN-α2a, s.c. IL-2, and i.v. 5-fluorouracil (5-FU) (n=235 pts) or (C) s.c. IFN-α2a, s.c. IL-2, and i.v. 5-FU combined with p.o. 13-cis-retinoic acid (13cRA) (n=88 pts). Kaplan–Meier survival analysis, log-rank statistics, and Cox regression analysis were employed to identify risk factors and to create a multiple risk factor model. The following pretreatment risk factors were identified by univariate analysis: (1) three and more metastatic sites, (2) presence of liver, lymph node or bone metastases, (3) neutrophil count ⩾6500 cells μl−1, (4) serum lactate dehydrogenase level (LDH) ⩾220 U l−1, and (5) serum C-reactive protein level (CRP) ⩾11 mg l−1. Cox regression analysis with forward stepwise variable selection identified neutrophil count as the major prognostic factor (hazard ratio=1.9, P<0.001), while serum levels of LDH and CRP, time between diagnosis of tumour and onset of metastatic disease, number of metastatic sites, and bone metastases were significant but somewhat less important prognostic variables within the multiple risk factor model (hazard ratio ⩽1.5). Patients were assigned to one of the three risk groups according to cumulative risk defined as the sum of simplified risk s.c.ores for six pretreatment variables. Low-, intermediate-, and high-risk patients achieved a median overall survival of 32+ months (95% CI 24, 43; 5-year survival of 27%), 18+ months (95% CI 15, 20; 5-year survival of 11%), and 8+ months (95% CI 6, 10; 5-year survival of 5%), respectively. These prognostic categories are helpful both in individual patient care and in the assessment of patients entering prospective clinical trials

Exposure to bisphosphonates and risk of common non-gastrointestinal cancers: series of nested case–control studies using two primary-care databases

Background: Bisphosphonates are the most commonly prescribed osteoporosis drugs but long-term effects are unclear, although antitumour properties are known from preclinical studies. Methods: Nested case–control studies were conducted to investigate bisphosphonate use and risks of common nongastrointestinal cancers (breast, prostate, lung, bladder, melanoma, ovarian, pancreas, uterus and cervical). Patients 50 years and older, diagnosed with primary cancers between 1997 and 2011, were matched to five controls using the UK practice-based QResearch and Clinical Practice Research Datalink (CPRD) databases. The databases were analysed separately and the results combined. Results: A total of 91 556 and 88 845 cases were identified from QResearch and CPRD, respectively. Bisphosphonate use was associated with reduced risks of breast (odds ratio (OR): 0.92, 95% confidence interval (CI): 0.87–0.97), prostate (OR: 0.87, 95% CI: 0.79–0.96) and pancreatic (OR: 0.79, 95% CI: 0.68–0.93) cancers in the combined analyses, but no significant trends with duration. For alendronate, reduced risk associations were found for prostate cancer in the QResearch (OR: 0.81, 95% CI: 0.70–0.93) and combined (OR: 0.84, 95% CI: 0.75–0.93) analyses (trend with duration P-values 0.009 and 0.001). There were no significant associations from any of the other analyses. Conclusion: In this series of large population-based case–control studies, bisphosphonate use was not associated with increased risks for any common non-gastrointestinal cancers

Chapter 12: Systematic Review of Prognostic Tests

A number of new biological markers are being studied as predictors of disease or adverse medical events among those who already have a disease. Systematic reviews of this growing literature can help determine whether the available evidence supports use of a new biomarker as a prognostic test that can more accurately place patients into different prognostic groups to improve treatment decisions and the accuracy of outcome predictions. Exemplary reviews of prognostic tests are not widely available, and the methods used to review diagnostic tests do not necessarily address the most important questions about prognostic tests that are used to predict the time-dependent likelihood of future patient outcomes. We provide suggestions for those interested in conducting systematic reviews of a prognostic test. The proposed use of the prognostic test should serve as the framework for a systematic review and to help define the key questions. The outcome probabilities or level of risk and other characteristics of prognostic groups are the most salient statistics for review and perhaps meta-analysis. Reclassification tables can help determine how a prognostic test affects the classification of patients into different prognostic groups, hence their treatment. Review of studies of the association between a potential prognostic test and patient outcomes would have little impact other than to determine whether further development as a prognostic test might be warranted

Reexamining the effects of gestational age, fetal growth, and maternal smoking on neonatal mortality

BACKGROUND: Low birth weight (<2,500 g) is a strong predictor of infant mortality. Yet low birth weight, in isolation, is uninformative since it is comprised of two intertwined components: preterm delivery and reduced fetal growth. Through nonparametric logistic regression models, we examine the effects of gestational age, fetal growth, and maternal smoking on neonatal mortality. METHODS: We derived data on over 10 million singleton live births delivered at ≥ 24 weeks from the 1998–2000 U.S. natality data files. Nonparametric multivariable logistic regression based on generalized additive models was used to examine neonatal mortality (deaths within the first 28 days) in relation to fetal growth (gestational age-specific standardized birth weight), gestational age, and number of cigarettes smoked per day. All analyses were further adjusted for the confounding effects due to maternal age and gravidity. RESULTS: The relationship between standardized birth weight and neonatal mortality is nonlinear; mortality is high at low z-score birth weights, drops precipitously with increasing z-score birth weight, and begins to flatten for heavier infants. Gestational age is also strongly associated with mortality, with patterns similar to those of z-score birth weight. Although the direct effect of smoking on neonatal mortality is weak, its effects (on mortality) appear to be largely mediated through reduced fetal growth and, to a lesser extent, through shortened gestation. In fact, the association between smoking and reduced fetal growth gets stronger as pregnancies approach term. CONCLUSIONS: Our study provides important insights regarding the combined effects of fetal growth, gestational age, and smoking on neonatal mortality. The findings suggest that the effect of maternal smoking on neonatal mortality is largely mediated through reduced fetal growth

Prognostic markers in cancer: the evolution of evidence from single studies to meta-analysis, and beyond

In oncology, prognostic markers are clinical measures used to help elicit an individual patient's risk of a future outcome, such as recurrence of disease after primary treatment. They thus facilitate individual treatment choice and aid in patient counselling. Evidence-based results regarding prognostic markers are therefore very important to both clinicians and their patients. However, there is increasing awareness that prognostic marker studies have been neglected in the drive to improve medical research. Large protocol-driven, prospective studies are the ideal, with appropriate statistical analysis and clear, unbiased reporting of the methods used and the results obtained. Unfortunately, published prognostic studies rarely meet such standards, and systematic reviews and meta-analyses are often only able to draw attention to the paucity of good-quality evidence. We discuss how better-quality prognostic marker evidence can evolve over time from initial exploratory studies, to large protocol-driven primary studies, and then to meta-analysis or even beyond, to large prospectively planned pooled analyses and to the initiation of tumour banks. We highlight articles that facilitate each stage of this process, and that promote current guidelines aimed at improving the design, analysis, and reporting of prognostic marker research. We also outline why collaborative, multi-centre, and multi-disciplinary teams should be an essential part of future studies