The purpose of this article is to present some of the challenges the trial statistician meets when designing a clinical trial of the head and neck cancer. In recent years, the field of head and neck ...cancer has been facing some exciting evolutions, such as the arrival of newly targeted therapies and findings of disease causality and prognosis. These evolutions are accompanied by challenges in trial methodology that continue even today, and will most likely grow in importance in the future. This article focuses essentially on the design of phase III trials and discusses three major topics: should the trial be designed for a broad or a targeted population? Is there a concern for lack of equipoise and if so, how will it affect the trial results? What are the key elements that need to be taken into consideration when choosing, defining, and measuring the primary endpoint?
For the Extreme Ultraviolet Imager (EUI) of the Solar Orbiter mission, to be launched in 2017, CMOS active pixel sensor (APS) prototypes have been developed with several test pixel designs. A set of ...measurements was carried out to evaluate their performance characteristics in visible and in extreme ultraviolet wavelengths. We present the results of measurement campaigns that lead to the selection of a preferred pixel design in regard to the scientific performance requirements of the EUI flight model detectors, i.e., back-thinned CMOS APS devices of 2048 × 2048 and 3072 × 3072 pixel formats with a 10-μm pixel pitch.
Gene expression data obtained in large studies hold great promises for discovering disease signatures or subtypes through data analysis. It is also prone to technical variation, whose removal is ...essential to avoid spurious discoveries. Because this variation is not always known and can be confounded with biological signals, its removal is a challenging task. Here we provide a step-wise procedure and comprehensive analysis of the MINDACT microarray dataset. The MINDACT trial enrolled 6693 breast cancer patients and prospectively validated the gene expression signature MammaPrint for outcome prediction. The study also yielded a full-transcriptome microarray for each tumor. We show for the first time in such a large dataset how technical variation can be removed while retaining expected biological signals. Because of its unprecedented size, we hope the resulting adjusted dataset will be an invaluable tool to discover or test gene expression signatures and to advance our understanding of breast cancer.
Abstract The aim of this randomized phase II study was to evaluate the anti-tumor activity and safety of capecitabine and vinorelbine in patients with metastatic breast cancer pretreated with taxanes ...and anthracyclines. We planned to randomize 72 patients to capecitabine 1250 mg/m2 orally bid days 1–14 or vinorelbine 30 mg/m2 i.v. days 1 and 8, both given every 3 weeks. The study was stopped due to poor accrual with 47 patients enrolled. Responses were seen in 2/23 patients treated with capecitabine (8.7%; 95% CI 1.1–29.0) and 3/24 patients treated with vinorelbine (12.5%; 95% CI 2.7–32.4). Median progression-free survival was 2.8 and 2.6 months, and median overall survival was 9.3 and 11.0 months, in the capecitabine and vinorelbine arms, respectively. There was more hematologic toxicity, neurotoxicity, and nausea/vomiting with vinorelbine and more diarrhea and hand-foot syndrome with capecitabine. The anti-tumor activity of capecitabine and vinorelbine seems to be comparable, but the toxicity profiles are different.
BackgroundThe European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS), a tool to assess the magnitude of clinical benefit from new cancer ...therapies. Grading is guided by a dual rule comparing the relative benefit (RB) and the absolute benefit (AB) achieved by the therapy to prespecified threshold values. The ESMO-MCBS v1.0 dual rule evaluates the RB of an experimental treatment based on the lower limit of the 95%CI (LL95%CI) for the hazard ratio (HR) along with an AB threshold. This dual rule addresses two goals: inclusiveness: not unfairly penalising experimental treatments from trials designed with adequate power targeting clinically meaningful relative benefit; and discernment: penalising trials designed to detect a small inconsequential benefit.MethodsBased on 50 000 simulations of plausible trial scenarios, the sensitivity and specificity of the LL95%CI rule and the ESMO-MCBS dual rule, the robustness of their characteristics for reasonable power and range of targeted and true HRs, are examined. The per cent acceptance of maximal preliminary grade is compared with other dual rules based on point estimate (PE) thresholds for RB.ResultsFor particularly small or particularly large studies, the observed benefit needs to be relatively big for the ESMO-MCBS dual rule to be satisfied and the maximal grade awarded. Compared with approaches that evaluate RB using the PE thresholds, simulations demonstrate that the MCBS approach better exhibits the desired behaviour achieving the goals of both inclusiveness and discernment.ConclusionsRB assessment using the LL95%CI for HR rather than a PE threshold has two advantages: it diminishes the probability of excluding big benefit positive studies from achieving due credit and, when combined with the AB assessment, it increases the probability of downgrading a trial with a statistically significant but clinically insignificant observed benefit.
Abstract We have performed a retrospective analysis to evaluate the impact of age, using a 70 year cutoff, on the safety and efficacy of pegylated liposomal doxorubicin (Caelyx™) given at 60 mg/m2 ...every 6 weeks (treatment A) or 50 mg/m2 every 4 weeks (treatment B) to 136 metastatic breast cancer patients in two EORTC trials, of whom 65 were 70 years of age or older. No difference in terms of toxicity was observed between younger and older patients treated with the 4-week schedule, while a higher incidence of hematological toxicity, anorexia, asthenia, and stomatitis was observed in older patients when the 6-week schedule was used. Antitumor activity was not affected by age. In the older cohort of patients, no dependence was found between the incidence of grade 3–4 toxicity or antitumor activity and patients’ baseline performance status, number and severity of comorbidities, or number of concomitant medications. The higher therapeutic index of Caelyx 50 mg/m2 every 4 weeks makes it, of the two dose schedules investigated, the preferred regimen in the elderly.
Abstract Background and Methods The optimal treatment of locally advanced breast cancer (LABC) remains undetermined. We analyzed factors influencing local therapy in LABC in a pooled material ...including three large clinical series. Results Of a total of 787 patients, local therapy was given in 604, surgery in 184, radiotherapy in 69, and a combination thereof in 351. The use of local therapy was related to younger age, lower clinical T and N stage, no skin involvement and no progression during induction chemotherapy. The use of surgery was related to younger age, lower clinical T and N stage, no clinical skin involvement and response to induction chemotherapy. The use of postoperative radiotherapy was correlated with larger tumor size, higher number of positive lymph nodes, positive surgical margin, extracapsular lymph node extension, lymphatic vessel invasion and skin involvement. Conclusions The most frequent local therapy in LABC remains a combination of surgery and radiotherapy. Clinical and pathological characteristics influence the type of local treatment.
The present article reviews the randomized trials contributing to the establishment of current standards for the treatment of head and neck cancer. It provides critical analysis of their methodology ...in order to facilitate future trial design.
From a prognosis perspective, head and neck cancers are a heterogeneous group of diseases. Following a number of randomized clinical trials evaluating the role of chemotherapy in the induction, concomitant and adjuvant settings, there has been considerable improvement in the treatment of locally advanced head and neck cancers during the last decade. It is, however, difficult to interpret and compare the results optimally and to build on efficient trial designs as most of the trials included patients with different levels of essential prognostic factors.
All key randomized trials will be reviewed according to eligibility criteria, subgroup issues, trial power and historical controls. Methodological interpretation and possible plans for the next generation of clinical trials will be presented.
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