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In a study of 127 patients with advanced measurable pancreatic cancer, objective response rates of 2% (melphalan), 10% (5-FU and methyl-CCNU), and 7% (5-FU, methyl-CCNU, and streptozocin) were achieved. No responses occurred in the 28 patients treated with VP-16-213 who had already received prior chemotherapy. Toxicity was greater for the two- and three-drug combinations than for melphalan. There was no difference in survival following use of the three treatment regimens. Further studies are needed to develop effective chemotherapy for patients with cancer of the pancreas.

Evaluating treatment effects within different subsets of patients is a common practice in the analysis of individual randomized clinical trials. Such analyses are limited, however, by the number of patients available. Overviews, by providing evidence based on large numbers of patients, can be useful for overcoming the difficulties of detecting therapeutic effects within subsets of patients. However, inconsistent subset definitions, misclassification of patients, and incomplete availability of patient subsets from the trials included in the overview bias the estimates of effect size. Separate analyses of subsets of studies are also possible within an overview. Studies being pooled generally differ with respect to treatments applied, control groups, patient eligibility, quality control, study conduct, and follow-up maturity. Separate comparisons within subsets defined by these features will be misinterpreted unless confounding factors are recognized. Indirect comparisons between overviews have the same informative value as nonrandomized trials with historical controls.

When patients have been randomized between different sets of treatments the treatment groups are not strictly comparable. However, if one can assume that biases which are introduced affect the outcome additively, then one can compare treatments across these institutional options. This is illustrated for dichotomous response data and censored survival data. We show how the sample size must be increased to allow for this analysis and how the randomization should be weighted to obtain the best power. These results have application to simultaneous trials by different cooperative groups which have one or more common treatment arms.

The use of adjuvant chemotherapy for treating patients with operable breast cancer remains a worldwide controversy. Using the data from published randomized control trials with a minimum two-year follow-up, pooled estimates of relapse-free survival rates and overall survival rates were calculated. Relapse-free survival rates were improved by 12.5% (95% confidence interval [CI] +/- 4.5%) at three years and by 8% (CI +/- 6%) at five years, with studies using multiple agents showing a greater effect. A significant advantage was also present in overall survival rates at three years, but only for studies involving multiple agents (4% +/- 3.5%). Results from combining data for other types of trials were inconclusive. The use of this method is presented to illustrate its value as an explicit and systematic one for combining data from several randomized control trials in assessing a therapeutic controversy.

DNA index and S-phase fraction of 490 primary breast carcinomas were measured by flow cytometry, using paraffin-embedded tissue as a starting point. All patients had involvement of axillary lymph nodes and all were randomized onto one of the Ludwig Breast Cancer Trials I-IV between July 1978 and August 1981. The presence of an abnormal DNA stemline correlated with involvement of four or more axillary lymph nodes (P = 0.09), postmenopausal status (P = 0.008), estrogen receptor negativity (P = 0.03), and high tumor grade (P = 0.0005). Disease-free and overall survival for these patients was worse than for those with tumors of normal DNA content, but DNA aneuploidy did not have independent prognostic significance when allowance was made for its correlation with other prognostic features. The percentage of cells in S phase, which is an index of cell proliferation, was also analyzed in 285 DNA histograms considered to be capable of giving a valid estimate. Disease-free survival for 154 patients with S phase less than or equal to 10% was significantly longer than for those with S phase greater than 10% (P = 0.0008). S-phase greater than 10% was strongly correlated with high tumor grade (P less than 0.00001) and abnormal DNA index (P less than 0.00001) but only weakly correlated with nodal, hormone receptor, and menopausal status. Multivariate analysis using a Cox proportional hazard model suggested that the prognostic significance of the percentage of S phase was related to the association with tumor grade. Because it gives rapid, objectively determined information about biological aggressiveness DNA flow cytometry may well establish a role in routine clinical practice, but further technical refinements are required before it can be used for treatment decision making in nodes positive early breast cancer patients.

We prospectively assigned 289 consecutive children with acute lymphoblastic leukemia to receive one of two treatment programs on the basis of the presence or absence of certain risk factors at the time of diagnosis. Patients at high risk (62 percent of the total) had one or more of the following risk factors: age below two or above nine years, a white-cell count of 20,000 per cubic millimeter or more, the presence of T-cell immunologic markers, radiologic evidence of a mediastinal mass, and involvement of the central nervous system. Patients in both the standard-risk and high-risk groups were treated for two years, receiving intensive remission-induction therapy, central nervous system prophylaxis, weekly administration of high-dose asparaginase, and multiple-drug continuation therapy (which in the high-risk group included doxorubicin and a larger dose of prednisone). At a median follow-up of 35 months, the mean (+/- SE) event-free survival rates at four years among the patients in the standard-risk and high-risk groups were 86 +/- 4 percent and 71 +/- 4 percent, respectively (P = 0.003), for a total event-free survival of 77 +/- 3 percent. Within the high-risk group, the white-cell count at diagnosis and the sex of the patient were not significant prognostic indicators, but age below 12 months at diagnosis was associated with a very poor outcome. As compared with previous methods, this treatment program using four-drug induction and intensive asparaginase therapy has resulted in improved event-free survival in children with acute lymphoblastic leukemia.

An endpoint, time without symptoms of disease and toxicity of treatment (TWiST), is defined to provide a single measure of length and quality of survival. Time with subjective side effects of treatment and time with unpleasant symptoms of disease are subtracted from overall survival time to calculate TWiST for each patient. The purpose of this paper is to describe the construction of this endpoint, and to elaborate on its interpretation for patient care decision-making. Estimating the distribution of TWiST using actuarial methods is shown by simulation studies to be biased as a result of induced dependency between TWiST and its censoring distribution. Considering the distribution of TWiST accumulated within a specified time from start of therapy, L, allows one to reduce this bias by substituting estimated TWiST for censored values and provides a method to evaluate the "payback" period for early toxic effects. Quantile distance plots provide graphical representations for treatment comparisons. The analysis of Ludwig Trial III evaluating toxic adjuvant therapies versus a no-treatment control group for postmenopausal women with node-positive breast cancer illustrates the methodology.