Disease volumes as a marker for patient response in malignant pleural mesothelioma.

BACKGROUND: The goal of this study was to create a comprehensive model for malignant pleural mesothelioma patient survival utilizing continuous, time-varying estimates of disease volume from computed tomography (CT) imaging in conjunction with clinical covariates. PATIENTS AND METHODS: Serial CT scans were obtained during the course of clinically standard chemotherapy for 81 patients. The pleural disease volume was segmented for each of the 281 CT scans, and relative changes in disease volume from the baseline scan were tracked over the course of serial follow-up imaging. A prognostic model was built using time-varying disease volume measurements in conjunction with clinical covariates. RESULTS: Over the course of treatment, disease volume decreased by an average of 19%, and median patient survival was 12.6 months from baseline. In a multivariate survival model, changes in disease volume were significantly associated with patient survival along with disease histology, Eastern Cooperative Oncology Group performance status, and presence of dyspnea. CONCLUSIONS: Analysis of the trajectories of disease volumes during chemotherapy for patients with mesothelioma indicates that increasing disease volume was significantly and independently associated with poor patient prognosis in both univariate and multivariate survival models.

Patterns of missing mini mental status exam (MMSE) in radiation therapy oncology group (RTOG) brain cancer trials.

The Mini Mental Status Exam (MMSE) instrument has been commonly used in the Radiation Therapy Oncology Group (RTOG) to assess mental status in brain cancer patients. Evaluating patient factors in relation to patterns of incomplete MMSE assessments can provide insight into predictors of missingness and optimal MMSE collection schedules in brain cancer clinical trials. This study examined eight RTOG brain cancer trials with ten treatment arms and 1,957 eligible patients. Patient data compliance patterns were categorized as: (1) evaluated at all time points (Complete), (2) not evaluated from a given time point or any subsequent time points but evaluated at all the previous time points (Monotone drop-out), (3) not evaluated at any time point (All missing), and (4) all other patterns (Mixed). Patient characteristics and reasons for missingness were summarized and compared among the missing pattern groups. Baseline MMSE scores and change scores after radiation therapy (RT) were compared between these groups, adjusting for differences in other characteristics. There were significant differences in frequency of missing patterns by age, treatment type, education, and Zubrod performance status (ZPS; P < 0.001). Ninety-two percent of patients were evaluated at least once: seven percent of patients were complete pattern, 49% were Monotone pattern, and 36% were mixed pattern. Patients who received RT only regimens were evaluated at a higher rate than patients who received RT + other treatments (49-64% vs. 27-45%). Institutional error and request to not be contacted were the most frequent known reasons for missing data, but most often, reasons for missing MMSE was unspecified. Differences in baseline mean MMSE scores by missing pattern (Complete, Monotone dropout, Mixed) were statistically significant (P < 0.001) but differences were small (<1.5 points) and significance did not persist after adjustment for age, ZPS, and other factors related to missingness. Post-RT change scores did not differ significantly by missing pattern. While baseline and change scores did not differ widely by missing pattern for available measurements, incomplete data was common and of unknown reason, and has potential to substantially bias conclusions. Higher compliance rates may be achievable by addressing institutional compliance with assessment schedules and patient refusal issues, and further exploration of how educational and health status barriers influence compliance with MMSE and other tools used in modern neurocognitive batteries.

Outcomes among African-Americans and Caucasians in colon cancer adjuvant therapy trials: findings from the National Surgical Adjuvant Breast and Bowel Project.

BACKGROUND: African-Americans generally have lower survival rates from colon cancer than Caucasian Americans. This disparity has been attributed to many sources, including diagnosis at later disease stage and other unfavorable disease features, inadequate treatment, and socioeconomic factors. The randomized clinical trial setting ensures similarity in disease stage and a uniform treatment plan between blacks and whites. In this study, we evaluated survival and related end points for African-American and Caucasian patients with colon cancer participating in randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP) to determine whether outcomes were less favorable for African-Americans. METHODS: The study included African-American (n = 663) or Caucasian (n = 5969) patients from five serially conducted, randomized clinical trials of the NSABP. We compared recurrence-free survival, disease-free survival (recurrence, new primary cancer, or death), and survival (death from any cause) between blacks and whites by using statistical modeling to account for differences in patient and disease characteristics between the groups. Statistical tests were two-sided. RESULTS: Dukes' stage and number of positive lymph nodes were remarkably similar between African-American and Caucasian patients in each trial. Over all trials combined, an 8% (95% confidence interval [CI] = -6% to 25%; P =.27) excess risk of colon cancer recurrence that was not statistically significant was observed for blacks. A greater disparity in survival was seen, with blacks experiencing a statistically significant 21% (95% CI = 6%-37%; P =.004) greater risk of death. Treatment efficacy appeared similar between the groups. CONCLUSIONS: While the overall survival prognosis was less favorable for African-Americans compared with Caucasians in these trials, other outcomes measured were considerably more similar than those seen in the population at large, suggesting that earlier detection and adjuvant therapy could appreciably improve colon cancer prognosis for African-Americans. Continued investigations into causes of the deficits noted are warranted.

Efficacy of systemic adjuvant therapy for breast cancer in African-American and Caucasian women.

Observed variations in breast cancer survival by racial/ethnic background have been attributed to many factors, including differences in clinical and pathologic disease features at diagnosis and economic resource inequities that may affect treatment access and quality. In this report, we examine outcomes for African-American and Caucasian breast cancer patients participating in selected randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP) to determine whether prognosis or efficacy of systemic adjuvant therapy differed between these groups. Randomized clinical trials offer the advantages of a similar disease stage and a uniform treatment plan for all participants. Patients from four NSABP trials enrolling patients from 1982 through 1994 with axillary lymph node-negative disease (543 African-American and 7582 Caucasian) and three trials enrolling patients from 1984 through 1991 with axillary lymph node-positive disease (548 African-American and 4986 Caucasian) were included. Disease-free survival (DFS), which was defined as time on study free of breast cancer recurrence, second primary cancer, or death preceding these events, and survival risk ratios (RRs) with two-sided 95% confidence intervals (CIs) for African-Americans versus Caucasians were computed from Cox proportional hazards models that included relevant prognostic covariates. Treatment benefits for the therapies evaluated in these trials were estimated separately for African-Americans and for Caucasians. Among patients with lymph node-negative disease, African-Americans had similar DFS rates to Caucasians (African-American/Caucasian RR = 1.06, 95% CI = 0.92 to 1.23) but had modestly greater mortality rates (RR = 1.21, 95% CI = 1.01 to 1.46). Among lymph node-positive patients, DFS was similar (RR = 1.04, 95% CI = 0.93 to 1.17) and survival was again less favorable for African-Americans (RR = 1.18 95% CI = 1.03 to 1.34). Survival excluding deaths most likely attributable to causes other than cancer was similar between African-Americans and Caucasians (RR = 1.08 [95% CI = 0.88 to 1.33] for lymph node-negative patients and RR = 1.09 [95% CI = 0.96 to 1.25] for lymph node-positive patients). Among lymph node-negative and lymph node-positive patients, African-Americans and Caucasians realized comparable benefit from either the addition of chemotherapy or tamoxifen to surgery alone or the addition of chemotherapy to tamoxifen. In summary, African-American women and Caucasian women who were diagnosed at a comparable disease stage and were similarly treated tended to experience similar breast cancer prognosis. However, a mortality deficit persisted for African-American women relative to Caucasian women, which may be in part due to greater mortality from noncancer causes among African-Americans. Benefit from systemic adjuvant therapy for recurrence and mortality reduction was comparable between African-Americans and Caucasians. This study and investigations in other health-care settings suggest that African-American women and Caucasian women with breast cancer derive a similar benefit from systemic adjuvant therapy when it is administered in accordance with their clinical and pathologic disease presentation.

Contamination of individuals by radon daughters: a preliminary study.

Body radon daughter contamination reflects relative individual respiratory exposures to radon daughters; counts can be related both to household radon levels and to lung cancer risk factors such as sex and tobacco smoking. Radon daughters were counted by gamma spectroscopy from 180 adult residents of eastern Pennsylvania. A seven-position, 35-min scan was conducted in a mobile body counter, generally during afternoon or evening hours. Track-etch detectors for household radon were distributed, and were recovered from 80% of the subjects. Over 75% of the population had environmentally enhanced radon daughter contamination. House radon levels were strongly related, as anticipated, to radon daughter contamination in the 112 subjects for whom both sets of measurements were available (p less than .001); basement measurements were as strongly related to personal contamination as were living area measurements; bedroom measurements were slightly more strongly correlated. Both sex (p less than .02) and cigarette smoking (p less than .01) significantly modified the relationships, after nonlinear adjustment for travel times. Using a logarithmic model, a given house living-area radon level was associated in females with body contamination by radon daughters 2-3 times that in males. Nonsmokers had 2-4 times higher levels of contamination than smokers. Results are for the total of internal and external contamination, these being highly correlated in preliminary experiments. Time usage and activity patterns of the subjects are believed to be important in explaining these findings, and may become important variables in radon risk assessment.

Differences in breast cancer prognosis among African-American and Caucasian women.

This review explores factors potentially contributing to the disparity in survival after breast cancer between African-American and Caucasian women in the United States. A number of factors have been implicated as the cause of poorer survival for black women, including clinical and pathologic features of the disease that are indicative of poor prognosis, economic resource inequities, and differences in treatment access and efficacy. The latter is explored in detail using data from the National Surgical Adjuvant Breast and Bowel Project (NSABP), a nationwide multicenter clinical trials group for breast and colorectal cancers. Key studies into the disparity in breast cancer survival are reviewed according to proposed principal determinants of poorer outcome for black women. Results among black and white women participating in several randomized NSABP clinical trials are also presented. Primary endpoints in those studies were clinical and pathologic disease characteristics at study entry, time to disease progression or new cancers, and total survival time after breast cancer diagnosis and treatment. In most studies reported in the literature, the primary explanatory factor alone, such as stage of disease at diagnosis, did not fully account for differences in outcome between groups; when additional factors were taken into account, however, prognoses became more similar. Results from the NSABP clinical trials similarly indicated that when stage of disease and treatment were comparable, outcomes for blacks did not differ markedly from those of whites. In summary, black women, diagnosed at comparable disease stage as white women and treated appropriately, tend to experience similar breast cancer prognoses and survival. However, important clinical and pathologic disease characteristics may continue to place certain women at increased risk of poorer outcome, and warrant continued study. The opportunity for increased clinical trial participation by black women is encouraged.

Methods for bounding the marginal survival distribution.

For time to event data with many potential failure types, one cannot uniquely determine the distribution of time to a specific event type, or marginal survival distribution, in the case where event types are mutually exclusive. In this paper we discuss several methods for estimating functions that bound the non-identifiable marginal survival distribution in the competing risks problem. We compute and compare bounds for data simulated from two bivariate survival distributions. Results show that the methods provide a suitable estimate of the marginal survival probability when one has specified dependence correctly. Data from a large clinical trial for breast cancer illustrate the methods.

Prognosis among African-American women and white women with lymph node negative breast carcinoma: findings from two randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP).

BACKGROUND: A disparity in breast carcinoma survival between African-American and white women has been noted over the past several decades. A major factor implicated in this disparity is stage of disease at diagnosis. In this study, survival and related endpoints were examined among African-American women and white women with lymph node negative breast carcinoma who participated in two randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP). METHODS: Patients from two studies, one conducted among patients with estrogen receptor (ER) negative tumors and the other among patients with ER positive tumors, were included. Study goals were to determine whether African-Americans and whites had comparable outcomes, accounting for ER status and differences in patient characteristics at diagnosis, and to determine whether treatment response was similar for African-Americans and whites. RESULTS: Five-year survival rates were 83% for African-Americans and 85% for whites among ER negative patients, and 93% for African-Americans and 92% for whites among ER positive patients. Rates of disease free survival (DFS) (i.e., time to disease recurrence, second primary cancer, or death) were 71% for African-Americans and 74% for whites at 5 years among ER negative patients, and 81% for African-Americans and 80% for whites among ER positive patients. African-Americans tended to have less favorable baseline prognostic characteristics. Adjusted relative risk (RR) estimates indicated similar prognosis for African-Americans compared with whites for mortality (African-American/white RR = 1.02 with 95% confidence interval [CI], 0.66-1.56 among ER negative patients; RR = 1.14 with 95% CI, 0.84-1.54 among ER positive patients) and DFS (RR = 0.98 with 95% CI, 0.70-1.37 for ER negative patients; RR = 0.96 with 95% CI, 0.75-1.22 for ER positive patients). Estimated percent reductions in DFS events for patients receiving adjuvant therapy were 32% for ER negative African-Americans, 36% for ER negative whites, 20% for ER positive African-Americans, and 39% for ER positive whites. CONCLUSIONS: African-American and white patients with localized breast carcinoma had similar outcomes and benefited equally from systemic therapy. These results suggest that early detection and appropriate therapy among African-American patients could result in a reduction in the current disparity in breast carcinoma mortality between African-Americans and whites.

Early stopping of a clinical trial when there is evidence of no treatment benefit: protocol B-14 of the National Surgical Adjuvant Breast and Bowel Project.

Although several randomized clinical trials in the 1980s indicated a benefit from the use of tamoxifen in the treatment of early-stage breast cancer, questions have remained regarding the optimal duration of drug administration. In 1982, the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated a randomized trial to compare 5 years of tamoxifen to placebo among breast cancer patients with estrogen receptor-positive tumors and no evidence of axillary node involvement. By 1987, evidence of a substantial benefit for tamoxifen led the NSABP to extend this trial to determine whether longer duration tamoxifen therapy would be additionally beneficial. This study randomized patients who had completed 5 years of tamoxifen free of breast cancer recurrence or other events to either tamoxifen or placebo for an additional 5 years. By 1994, 1172 women had entered the study and accrual was closed. In late 1995, the trial was terminated on the basis of interim findings indicating that a benefit for continuing tamoxifen would not be realized. The closure has prompted controversy among cancer researchers, because there are currently at least three tamoxifen duration trials in progress, whereas results from two other studies evaluating 5-year duration therapy versus longer therapy were recently published. Here, we provide details of the statistical rationale contributing to our decision to recommend early closure of the study. We then consider other possible approaches to assessing the appropriateness of early termination in the face of evidence against a benefit, including Bayesian methods, which can be used to incorporate a range of prior beliefs regarding the efficacy of a treatment with accruing information from the trial. We also briefly discuss results of the other published studies.