Showing papers by "Donald A. Berry published in 1994"

c-erbB-2 Expression and Response to Adjuvant Therapy in Women with Node-Positive Early Breast Cancer

Abstract: Background The role of molecular markers in predicting the response to treatment of breast cancer is poorly defined. The Cancer and Leukemia Group B (CALGB) conducted a randomized adjuvant-chemotherapy trial (CALGB 8541) comparing three doses (high, moderate, and low) of cyclophosphamide, doxorubicin, and fluorouracil in 1572 women with node-positive breast cancer. This study (CALGB 8869) was designed to determine whether the DNA index, the S-phase fraction, c-erbB-2 expression, or p53 accumulation could be used as a marker to identify a subgroup of patients more likely than others to benefit from high doses of chemotherapy. Methods Tissue blocks were obtained from 442 patients randomly selected from the larger CALGB trial. Paraffin sections from the primary lesions were analyzed for DNA content, S-phase fraction, c-erbB-2 expression, and p53 accumulation. Results Patients randomly assigned to the high-dose regimen of adjuvant chemotherapy had significantly longer disease-free and overall survival if thei...

Overexpression of p53 and HER-2/neu Proteins as Prognostic Markers in Early Stage Breast Cancer

Abstract: Objective Overexpression of the p53 and HER-2/neu oncogenes are the two most common genetic abnormalities associated with breast cancer. Shorter survival time has been reported in patients with tumors with p53 or HER-2/neu. This report analyzes a retrospective cohort of early stage breast cancers for both oncogenes and relates overexpression to clinicopathologic parameters and survival. Methods Immunostaining for p53 and HER-2/neu was performed on 230 paraffin-embedded specimens of stage I and II breast cancers diagnosed and treated at Duke University Medical Center between 1984 and 1987. Positive staining for both p53 and HER-2/neu in paraffin-embedded tissues indicates an underlying genetic abnormality: point mutations in the p53 gene and amplification of the HER-2/neu gene. Results In this cohort of patients, 24% were positive for p53 and 17% for HER-2/neu. Four per cent were positive for both oncogenes. Significant correlations were found between p53 immunostaining and increasing tumor size, stage, and low estrogen and progesterone receptor contents. Univariate analysis showed that p53 and HER-2/neu were indicators of overall and failure-free survival. An additive effect on survival was observed in patients with both oncogene abnormalities. Nodal status, HER-2/neu, and p53 all attained independent prognostic value in a multivariate analysis. Conclusions The p53 and HER-2/neu oncogenes have proven but limited prognostic value. An approach that combines several molecular genetic markers with established pathologic criteria may help physicians to make more accurate predictions of prognosis in patients with early stage breast cancer.

Group sequential clinical trials: a classical evaluation of Bayesian decision-theoretic designs

Abstract: Bayesian decision-theoretic designs for a clinical trial comparing two treatments for a disease with binary outcomes are developed and evaluated. The probability of successful outcome with treatment i is denoted by pi , i = 1, 2, and prior knowledge regarding each pi is assumed to follow a beta distribution. The pi are assumed to be independent. To facilitate comparison with frequentist clinical trial designs, we take a hypothesis-testing approach. The null hypothesis is δ 0, where δ 0 is the minimum treatment effect sought by the trial and δ = p 2 - p 1 is the true treatment difference. We use a simple terminal loss function reflecting the hypothesis-testing goal of the trial, and the total cost of the trial is the final sample size plus the terminal loss function. The stopping and decision rules that minimize the expectation of the total cost are determined by backward induction. Monte Carlo simulation is used to compare Bayesian and frequentist erro...

Stopping a clinical trial early: frequentist and Bayesian approaches applied to a CALGB trial in non-small-cell lung cancer.

Abstract: In May 1984, the Cancer and Leukemia Group B (CALGB) opened a phase III clinical trial for patients with stage III non-small-cell lung cancer (NSCLC). The experimental design entailed randomization of 240 patients equally to one of two treatments: radiotherapy alone or chemotherapy followed by radiotherapy. The original design was a fixed sample size design with the intent to analyse the results after 190 deaths. Shortly after the trial began, it was decided to apply group sequential concepts by using a truncated O'Brien-Fleming stopping rule, implemented via a Lan-DeMets α-spending function. A study monitoring committee was established to review the analyses as they were produced. The study was stopped at the fifth interim analysis in May 1987 after 155 eligible patients had been entered. This paper reviews the statistical and other considerations leading to this decision and presents later follow-up information on these patients. Some Bayesian alternatives to the standard frequentist approaches are also explored and it is demonstrated how these alternatives provide a natural way to address many of the issues raised in monitoring clinical trials.

Using Historical Controls in Clinical Trials: Application to ECMO

Abstract: Combining different types of information is problematic. Some information, such as historical data, should be discounted, perhaps subjectively. We consider merging historical information with data from a clinical trial. The goal is to ascertain treatment effect in the patient population of the clinical trial. We develop a method that uses patient characteristics and partially discounts the historical data. The result is a probability distribution concerning treatment benefit as it depends on patient characteristics. Such a distribution allows for addressing the question of whether additional clinical experimentation is appropriate.