Calibration and discriminatory accuracy of prognosis calculation for breast cancer with the online Adjuvant! program: A hospital-based retrospective cohort study

Background Adjuvant! is a web-based program that calculates individualised 10-year survival probabilities and predicted benefit of adjuvant systemic therapy. The Adjuvant! model has not been validated in any large European series. The aim of our study was to validate Adjuvant! in Dutch patients, investigating both its calibration and discriminatory accuracy. Methods Patients who were at least partly treated at the Netherlands Cancer Institute for breast cancer between 1987 and 1998 were included if they met the following criteria: tumour size T1 (≤2 cm), T2 (2–5 cm), or T3 (>5 cm), invasive breast carcinoma, with information about involvement of axillary lymph nodes available, no distant metastases, primary surgery, axillary staging, and radiotherapy according to national guidelines. Clinicopathological characteristics and adjuvant treatment data were retrieved from hospital records and medical registries and were entered into the Adjuvant! (version 8.0) batch processor with blinding to outcome. Endpoints were overall survival and the proportion of patients that did not die from breast cancer (breast-cancer-specific survival [BCSS]). Findings 5380 patients were included with median follow-up of 11•7 years (range 0•03–21•8). The 10-year observed overall survival (69•0%) and BCSS (78•6%) and Adjuvant! predicted overall survival (69•1%) and BCSS (77•8%) were not statistically different (p=0•87 and p=0•18, respectively). Moreover, differences between predicted and observed outcomes were within 2% for most relevant clinicopathological subgroups. In patients younger than 40 years, Adjuvant! overestimated overall survival by 4•2% (p=0•04) and BCSS by 4•7% (p=0•01). The concordance index, which indicates discriminatory accuracy at the individual level, was 0•71 for BCSS in the entire cohort. Interpretation Adjuvant! accurately predicted 10-year outcomes in this large-scale Dutch validation study and is of use for adjuvant treatment decision making, although the results may be less reliable in some subgroups. Funding Dutch National Genomics Initiative-Cancer Genomics Center, Dutch Cancer Society-KWF

Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer

PURPOSE The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome. PATIENTS AND METHODS PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models. RESULTS PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P &lt; .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P &lt; .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication. CONCLUSION First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings. </jats:sec

The Relevance of Child Phonology for a Developmentalist Theory of Language

Surgical oncolog

Effects of mammography screening under different screening schedules: Model estimates of potential benefits and harms

Background: Despite trials of mammography and widespread use, optimal screening policy is controversial. Objective: To evaluate U.S. breast cancer screening strategies. Design: 6 models using common data elements. Data Sources: National data on age-specific incidence, competing mortality, mammography characteristics, and treatment effects. Target Population: A contemporary population cohort. Time Horizon: Lifetime. Perspective: Societal. Interventions: 20 screening strategies with varying initiation and cessation ages applied annually or biennially. Outcome Measures: Number of mammograms, reduction in deaths from breast cancer or life-years gained (vs. no screening), false-positive results, unnecessary biopsies, and overdiagnosis. Results of Base-Case Analysis: The 6 models produced consistent rankings of screening strategies. Screening biennially maintained an average of 81% (range across strategies and models, 67% to 99%) of the benefit of annual screening with almost half the number of false-positive results. Screening biennially from ages 50 to 69 years achieved a median 16.5% (range, 15% to 23%) reduction in breast cancer deaths versus no screening. Initiating biennial screening at age 40 years (vs. 50 years) reduced mortality by an additional 3% (range, 1% to 6%), consumed more resources, and yielded more false-positive results. Biennial screening after age 69 years yielded some additional mortality reduction in all models, but overdiagnosis increased most substantially at older ages. Results of Sensitivity Analysis: Varying test sensitivity or treatment patterns did not change conclusions. Limitation: Results do not include morbidity from false-positive results, patient knowledge of earlier diagnosis, or unnecessary treatment. Conclusion: Biennial screening achieves most of the benefit of annual screening with less harm. Decisions about the best strategy depend on program and individual objectives and the weight placed on benefits, harms, and resource considerations. Primary Funding Source: National Cancer Institute