Clinical outcomes in men of diverse ethnic backgrounds with metastatic castration-resistant prostate cancer.

BACKGROUND: We have shown previously in multivariable analysis that black men had 19% lower risk of death than white men with metastatic castration-resistant prostate cancer (mCRPC) treated with a docetaxel and prednisone (DP)-based regimen. The primary goal of this analysis was to compare progression-free survival (PFS), biochemical PFS, ≥50% decline in prostate-specific antigen (PSA) from baseline and objective response rate (ORR) in white, black and Asian men with mCRPC treated with a DP-based regimen. PATIENTS AND METHODS: Individual patient data from 8820 mCRPC men randomized on nine phase III trials to a DP-containing regimen were combined. Race used in the analysis was based on self-report. End points were PFS, biochemical PSA, ≥50% decline in PSA from baseline and ORR. The proportional hazards and the logistic regression models were employed to assess the prognostic importance of race in predicting outcomes adjusting for established prognostic factors. RESULTS: Of 8820 patients, 7528 (85%) were white, 500 (6%) were black, 424 were Asian (5%) and 368 (4%) had race unspecified. Median PFS were 8.3 [95% confidence interval (CI) 8.2-8.5], 8.2 (95% CI 7.4-8.8) and 8.3 (95% CI 7.6-8.8) months in white, black and Asian men, respectively. Median PSA PFS were 9.9 (95% CI 9.7-10.4), 8.5 (95% CI 8.0-10.3) and 11.1 (95% CI 9.9-12.5) months in white, black and Asian men, respectively. CONCLUSIONS: We observed no differences in clinical outcomes by race and ethnic groups in men with mCRPC enrolled on these phase III clinical trials with DP.

Bone turnover biomarkers identify unique prognostic risk groups in men with castration resistant prostate cancer and skeletal metastases: Results from SWOG S0421.

BACKGROUND: Skeletal metastases often occur in men with castration-resistant prostate cancer (CRPC) where bone biomarkers are prognostic for overall survival (OS). In those with highly elevated markers, there is preferential benefit from bone-targeted therapy. In the phase IIIS0421 docetaxel +/- atrasentan trial, clinical covariates and bone biomarkers were analyzed to identify CRPC subsets with differential outcomes. SUBJECTS AND METHODS: Markers of bone resorption [N-telopeptide-NTx; pyridinoline-PYD] and formation [C-terminal collagen propeptide-CICP; bone alkaline phosphatase-BAP] were measured in pre-treatment sera. Bone biomarkers and clinical covariates were included in a Cox model for OS; bone markers were added in a stepwise selection process. Receiver operating characteristic (ROC) curves were constructed for risk factor models +/- bone markers. Significant variables were allowed to compete in a classification and regression tree (CART) analysis. Hazard ratios(HR) were calculated by comparing OS in each of the terminal nodes to a reference group in a Cox model. RESULTS: 750 patients were included. Each bone marker significantly contributed to the risk factor-adjusted OS Cox model, with higher levels associated with worse OS. BAP (HR = 1.15, p = 0.008), CICP (HR = 1.27, p < 0.001), and PYD (HR = 1.21, p = 0.047) in combination were significantly associated with OS. Prognostic accuracy was improved by addition of bone markers to clinical covariates. CART analysis selected CICP, BAP, hemoglobin, and pain score for the final OS model, identifying five prognostic groups. CONCLUSIONS: Elevated serum bone biomarker levels are associated with worse OS in bone-metastatic CRPC. Bone biomarkers can identify unique prognostic subgroups. These results further define the role of bone biomarkers in the design of CRPC trials.

Intraprostatic inflammation is positively associated with serum PSA in men with PSA <4 ng ml(-1), normal DRE and negative for prostate cancer.

BACKGROUND: Biopsies performed for elevated serum PSA often show inflammatory infiltrates. However, the influence of intraprostatic inflammation on serum PSA in men without biopsy indication and negative for prostate cancer has not been described in detail. METHODS: We studied 224 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) who underwent end-of-study biopsy per trial protocol, had PSA <4 ng ml(-1), normal digital rectal examination and a biopsy negative for cancer. We analyzed data from hematoxylin and eosin-stained slides containing a mean of three biopsy cores. Inflammation measures included the extent (percentage of tissue area with inflammation) and intensity (product of scores for extent and grade) of total, acute and chronic inflammation in the entire tissue area examined, and by tissue compartment. We calculated median measures of inflammation by prebiopsy serum PSA tertile (>0 to ≤0.8, >0.8 to ≤1.5 and >1.5 to <4.0 ng ml(-1)). We estimated the association between percentage of tissue area with inflammation and natural logarithm of PSA using linear regression adjusting for age at biopsy. RESULTS: Median percentage of tissue area with inflammation increased from 2 to 5 to 9.5% across PSA tertiles (P-trend <0.0001). For every 5% increase in tissue area with inflammation, log PSA increased by 0.061 ng ml(-1) (P=0.0002). Median extent and intensity scores increased across PSA tertiles in luminal and intraepithelial compartments for acute inflammation and in stromal and intraepithelial compartments for chronic inflammation (all P-trend ≤0.05). CONCLUSIONS: In men without clinical suspicion of prostate cancer, greater overall inflammation, luminal and intraepithelial acute inflammation and stromal and intraepithelial chronic inflammation were associated with higher serum PSA.

Non-parametric analysis of covariance for confirmatory randomized clinical trials to evaluate dose-response relationships.

In confirmatory randomized clinical trials that are designed to compare multiple doses of a test treatment with a control group and with one another, there are often statistical issues regarding compound hypotheses and multiple comparisons which need to be considered. In most cases the analysis plan needs a clear specification for the proposed order for conducting statistical tests (or for managing the overall significance level), which statistical methods will be used, and whether adjustment for covariates will be performed. There are several benefits of specifying non-parametric analysis of covariance (ANCOVA) for performing the primary confirmatory analyses. Only minimal assumptions are needed beyond randomization in the study design, whereas regression model based methods have assumptions about model fit for which departures may require modifications that are incompatible with a fully prespecified analysis plan. Non-parametric methods provide traditionally expected results of ANCOVA; namely, a typically small adjustment to the estimate for a treatment comparison (so as to account for random imbalance of covariates between treatment groups) and variance reduction for this estimate when covariates are strongly correlated with the response of interest. The application of non-parametric ANCOVA is illustrated for two randomized clinical trials. The first has a (3 x 4) factorial response surface design for the comparison of 12 treatments (that is, combinations of three doses of one drug and four doses of a second drug) for change in blood pressure; and the second example addresses the comparison of three doses of test treatment and placebo for time-to-disease progression. This clinical trial has comparisons among treatments made for a dichotomous criterion, Wilcoxon rank scores and averages of cumulative survival rates. In each example, the non-parametric covariance method provides variance reduction relative to its unadjusted counterpart.

Frailty in older adults: evidence for a phenotype.

BACKGROUND: Frailty is considered highly prevalent in old age and to confer high risk for falls, disability, hospitalization, and mortality. Frailty has been considered synonymous with disability, comorbidity, and other characteristics, but it is recognized that it may have a biologic basis and be a distinct clinical syndrome. A standardized definition has not yet been established. METHODS: To develop and operationalize a phenotype of frailty in older adults and assess concurrent and predictive validity, the study used data from the Cardiovascular Health Study. Participants were 5,317 men and women 65 years and older (4,735 from an original cohort recruited in 1989-90 and 582 from an African American cohort recruited in 1992-93). Both cohorts received almost identical baseline evaluations and 7 and 4 years of follow-up, respectively, with annual examinations and surveillance for outcomes including incident disease, hospitalization, falls, disability, and mortality. RESULTS: Frailty was defined as a clinical syndrome in which three or more of the following criteria were present: unintentional weight loss (10 lbs in past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity. The overall prevalence of frailty in this community-dwelling population was 6.9%; it increased with age and was greater in women than men. Four-year incidence was 7.2%. Frailty was associated with being African American, having lower education and income, poorer health, and having higher rates of comorbid chronic diseases and disability. There was overlap, but not concordance, in the cooccurrence of frailty, comorbidity, and disability. This frailty phenotype was independently predictive (over 3 years) of incident falls, worsening mobility or ADL disability, hospitalization, and death, with hazard ratios ranging from 1.82 to 4.46, unadjusted, and 1.29-2.24, adjusted for a number of health, disease, and social characteristics predictive of 5-year mortality. Intermediate frailty status, as indicated by the presence of one or two criteria, showed intermediate risk of these outcomes as well as increased risk of becoming frail over 3-4 years of follow-up (odds ratios for incident frailty = 4.51 unadjusted and 2.63 adjusted for covariates, compared to those with no frailty criteria at baseline). CONCLUSIONS: This study provides a potential standardized definition for frailty in community-dwelling older adults and offers concurrent and predictive validity for the definition. It also finds that there is an intermediate stage identifying those at high risk of frailty. Finally, it provides evidence that frailty is not synonymous with either comorbidity or disability, but comorbidity is an etiologic risk factor for, and disability is an outcome of, frailty. This provides a potential basis for clinical assessment for those who are frail or at risk, and for future research to develop interventions for frailty based on a standardized ascertainment of frailty.

Association of African-American ethnic background with survival in men with metastatic prostate cancer.

BACKGROUND: African-American men have earlier onset of prostate cancer, higher prostate-specific antigen (PSA) levels, more advanced stage at diagnosis, and higher mortality than white men. It is not known whether the poorer survival of African-American men with prostate cancer reflects their later stage at diagnosis or differences in the basic biology of their disease. To evaluate this question, we examined outcomes of African-American and white men with metastatic prostate cancer in the context of a randomized clinical trial. METHODS: Southwest Oncology Group Study 8894 was a randomized phase III trial that compared orchiectomy with or without flutamide in men with metastatic prostate cancer. Using data from 288 African-American and 975 white men in the trial, we conducted a proportional hazards regression analysis to determine if ethnicity was an independent predictor of survival. All statistical tests were two-sided. RESULTS: African-American men were more likely than white men to have extensive disease and bone pain and had poorer performance status, younger age at study entry, higher Gleason score, and higher PSA levels. After adjustment for these prognostic variables, the hazard ratio (HR) for all-cause mortality for African-American men relative to white men was 1.23 (P: =.018). Further adjustment for initial quality-of-life assessments also resulted in higher HRs associated with African-American ethnicity relative to white ethnicity (HR = 1.39; P: =.007). CONCLUSIONS: African-American men with metastatic prostate cancer have a statistically significantly worse prognosis than white men that cannot be explained by the prognostic variables explored in this study. These data should give increased impetus for efforts to detect the disease early in African-American men and for the development of more effective therapies based on potential biologic differences in this ethnic group.

Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Cardiovascular Health Study Collaborative Research Group.

BACKGROUND: Several epidemiological studies have associated depressive symptoms with cardiovascular disease. We investigated whether depressive symptoms constituted a risk for coronary heart disease (CHD) and total mortality among an apparently healthy elderly cohort. METHODS AND RESULTS: In a prospective cohort of 5888 elderly Americans (>/=65 years) who were enrolled in the Cardiovascular Health Study, 4493 participants who were free of cardiovascular disease at baseline provided annual information on their depressive status, which was assessed using the Depression Scale of the Center for Epidemiological Studies. These 4493 subjects were followed for 6 years for the development of CHD and mortality. The cumulative mean depression score was assessed for each participant up to the time of event (maximum 6-year follow-up). Using time-dependent, proportional-hazards models, the unadjusted hazard ratio associated with every 5-unit increase in mean depression score for the development of CHD was 1.15 (P:=0.006); the ratio for all-cause mortality was 1.29 (P:<0.0001). In multivariate analyses adjusted for age, race, sex, education, diabetes, hypertension, cigarette smoking, total cholesterol, triglyceride level, congestive heart failure, and physical inactivity, the hazard ratio for CHD was 1.15 (P:=0.006) and that for all-cause mortality was 1.16 (P:=0.006). Among participants with the highest cumulative mean depression scores, the risk of CHD increased by 40% and risk of death by 60% compared with those who had the lowest mean scores. CONCLUSIONS: Among elderly Americans, depressive symptoms constitute an independent risk factor for the development of CHD and total mortality.

Non-parametric covariance methods for incidence density analyses of time-to-event data from a randomized clinical trial and their complementary roles to proportional hazards regression.

The principal response criteria for many clinical trials involve time-to-event variables. Usual methods of analysis for this type of response criterion include product-limit estimators of cumulative survival for the treatment groups, (stratified) logrank tests to compare treatments, and proportional hazards regression models with treatment and relevant covariates. When adjustment for covariates is of some importance, the relative roles of these methods may be of some concern, particularly for confirmatory clinical trials which must provide convincing findings to regulatory agencies. Unadjusted methods may have lower power, but there are issues regarding adjustment for covariates that may be controversial. These issues include applicability of proportional hazards assumptions, whether the correct model has been specified, and whether there is parallelism between treatments for relationships with covariates. One way to address these issues is to use non-parametric analysis of covariance strategies with extensions to log incidence density estimation. The principal basis for this method is no association between covariates and treatment groups as provided by randomized assignment of patients to groups. The background theory and strategies for computation are described for this method. Aspects of its application are illustrated for a clinical trial with two treatment groups and 722 patients. The objective of analysis for this clinical trial is evaluation of treatment effects with and without adjustment for 22 a priori covariates and a stratification for three geographical regions.

Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction.

OBJECTIVE: APOE-epsilon4 increases the risk of cognitive decline, while elderly women who take estrogen may have less risk of cognitive decline. The authors sought to determine whether estrogen use modifies the association between APOE-epsilon4 and cognitive decline. METHOD: - As part of the Cardiovascular Health Study, 3,393 Medicare-eligible women (> or =65 years) were randomly selected and recruited from Sacramento County, CA; Washington County, MD; Forsyth County, NC; and Pittsburgh, PA. Cognitive testing was administered annually; the authors studied the 2,716 women with cognitive testing on > or =2 visits. They analyzed change in score on the Modified Mini-Mental State Examination (3MS) as a function of estrogen use, APOE genotype, and baseline common and internal carotid artery wall thickening. RESULTS: A total of 297 (11%) women were current estrogen users and 336 (12%) were past estrogen users. Over the 6-year average follow-up, baseline current users declined 1.5 points on the 3MS whereas never users declined 2.7 points (p = 0.023). Compared with epsilon4-negative women, epsilon4-positive women had a greater adjusted hazard ratio of cognitive impairment (3MS < 80), hazard risk [HR] = 1.47; 95% CI, 1.13 to 1.90. There was an interaction between estrogen use and epsilon4 presence (p = 0.037). Among epsilon4-negative women, current estrogen use reduced the risk of adjusted cognitive impairment compared with never users by almost half (HR = 0.59; 95% CI, 0.36 to 0.99), whereas, it did not reduce the risk among epsilon4-positive women (current use, HR = 1.33; 95% CI, 0.74 to 2.42). Compared with never use, current estrogen use was associated with less internal and common carotid wall thickening in epsilon4-negative women but not in epsilon4-positive women (p for interaction < 0.05 for both). Differences remained after adjusting for age, education, race, and stroke. CONCLUSIONS: Estrogen use was associated with less cognitive decline among epsilon4-negative women but not epsilon4-positive women. Potential mechanisms, including carotid atherosclerosis, by which epsilon4 may interact with estrogen and cognition warrant further investigation.

Docetaxel (Taxotere) and estramustine versus mitoxantrone and prednisone for hormone-refractory prostate cancer: scientific basis and design of Southwest Oncology Group Study 9916.

Hormone-refractory prostate cancer is the terminal step in the natural history of prostate cancer. To date, no chemotherapeutic agents have been shown to impact clinical outcome at this stage. Recently, the Food and Drug Administration approved the combination of mitoxantrone and prednisone based solely on its superior palliative effects as compared to steroids alone in 2 randomized trials. Progress in biologically driven drug development has led to the identification of several estramustine-based regimens that, although based on single institution experience, appear to have at least a comparable but very promising level of activity in hormone-refractory prostate cancer patients. One such combination, estramustine plus docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA), is particularly attractive because of its convenient schedule and side effect profile. To objectively assess the therapeutic benefit of this combination, the Southwest Oncology Group is initiating a randomized phase III trial comparing estramustine and docetaxel with the standard arm of mitoxantrone and prednisone using time to progression and survival as the primary end points. Secondary end points will include toxicity profiles, assessments of quality of life parameters, and magnitude of decline of prostate-specific antigen levels between the two treatment arms.

Increased blood glucose and insulin, body size, and incident colorectal cancer.

BACKGROUND: Abdominal obesity--an elevated level of visceral adipose tissue--has been linked to colorectal cancer. Furthermore, elevated levels of visceral adipose tissue have been associated with hyperinsulinemia, and insulin is a growth factor in the colon. We assessed whether waist circumference, a surrogate measure of visceral adipose tissue, and metabolic parameters associated with visceral adipose tissue were related to colorectal cancer. METHODS: In the Cardiovascular Health Study cohort, we examined the relationship of baseline measurements of body size, glucose, insulin, and lipoproteins to incident colorectal cancer. All P values are two-sided. RESULTS: Among 5849 participants, 102 incident cases of colorectal cancer were identified. Individuals in the highest quartile of fasting glucose had a nearly twofold increased risk of colorectal cancer (relative risk [RR] = 1.8; 95% confidence interval [CI] = 1.0-3.1), and the linear trend RR (LT RR = 1.2; 95% CI = 1.0-1.5) for fasting glucose level was statistically significant (P =. 02). Glucose and insulin levels 2 hours after oral glucose challenge also exhibited statistically significant associations with colorectal cancer (2-hour glucose levels: RR = 2.4 [95% CI = 1.2-4. 7]/LT RR = 1.3 [95% CI = 1.0-1.6; P =.02]; 2-hour insulin levels: RR = 2.0 [95% CI = 1.0-3.8]/LT RR = 1.2 [95% CI = 1.0-1.5; P =.04]). Analysis of fasting insulin levels suggested a threshold effect, with values above the median associated with colorectal cancer (RR = 1.6; 95% CI = 1.1-2.4; P =.02). Higher levels of waist circumference were also statistically significantly associated with colorectal cancer (RR = 1.9; 95% CI = 1.1-3.3; P =.02). CONCLUSIONS: These data provide, to our knowledge, the first direct evidence of an association between elevated visceral adipose tissue level, its associated metabolic effects, and colorectal cancer.

Nonparametric analysis of covariance for hypothesis testing with logrank and Wilcoxon scores and survival-rate estimation in a randomized clinical trial.

Many clinical trials have time-to-event variables as principal response criteria. When adjustment for covariates is of some importance, the relative role of methods for such analysis may be of some concern. For the Wilcoxon and logrank tests, there is an issue of how covariance adjustment can be nonparametric in the sense of not involving any further assumptions beyond those of the logrank and Wilcoxon test. Also of particular interest in a clinical trial is the estimation of the difference between survival probabilities for the treatment groups at several points in time. As with the Wilcoxon and logrank tests, there is no well known nonparametric way to incorporate covariate adjustment into such estimation of treatment effects for survival rates. We propose a method that enables covariate adjustment for hypothesis testing with logrank or Wilcoxon scores. Related extensions for applying covariate adjustment to estimation of treatment effects are provided for differences in survival-rate counterparts to Kaplan-Meier survival rates. The results represent differences in population average survival rates with adjustment for random imbalance of covariates between treatment groups. The methods are illustrated with a clinical trial example.

Severe disruptive vocalizers.

OBJECTIVES: To describe the most severe disruptive vocalizers in nursing facilities, in regard to their clinical and behavioral characteristics, staff responses, and treatments used, and to report on their prognosis over 6 months. DESIGN: A longitudinal cohort study. SETTING: One hundred seven skilled nursing facilities. PARTICIPANTS: The 203 residents who were among the two most disruptive vocalizers in their respective facilities and who vocalized at least 2 hours a day. MEASUREMENTS: Telephone interviews of licensed nursing staff who cared for the subjects, conducted at baseline, 2, 4, and 6 months. Data gathered included subject demographics, physical function, diagnoses, medication and restraint use, behavioral problems, vocalization characteristics, treatments used, and status at follow-up. RESULTS: Subjects tended to have dementia, to be dependent in most activities of daily living, to have multiple medical problems, to be physically restrained (48%), and to be taking psychotropic medication (76%). Nearly all (95%) were audible at least 50 feet away, with loudness associated with more severe cognitive impairment (OR 4.90, P = .001). When subjects who primarily made nonverbal noises ("screamers") were compared with those whose predominant expressions were words ("talkers"), hearing impairment, severe cognitive impairment, and greater dependency in activities of daily living characterized the screamers. Staff reported trying a variety of treatments with all subjects, often with little success. Two months after enrollment, 66% of surviving subjects vocalized fewer hours than at baseline, and 45% were rated as improved. Independent predictors of improvement included greater ADL independence, hearing and vision problems, shorter length of stay, urinary incontinence, and use of a treatment other than one-on-one interventions. Nearly one-quarter of subjects (23.4%) died within 6 months. Baseline factors associated independently with a higher probability of death included age, use of activity intervention, physical abusiveness, and absence of wandering. CONCLUSION: Severe disruptive vocalization is associated with severe cognitive and physical impairment and with a high probability of mortality within 6 months. Subcategorization of severe vocalizers by vocalization type or other associated factors may be useful for prognostic and treatment purposes.

Complementary nonparametric analysis of covariance for logistic regression in a randomized clinical trial setting.

In the randomized clinical trial setting, controlling for covariates is expected to produce variance reduction for the treatment parameter estimate and to adjust for random imbalances of covariates between the treatment groups. However, for the logistic regression model, variance reduction is not obviously obtained. This can lead to concerns about the assumptions of the logistic model. We introduce a complementary nonparametric method for covariate adjustment. It provides results that are usually compatible with expectations for analysis of covariance. The only assumptions required are based on randomization and sampling arguments. The resulting treatment parameter is a (unconditional) population average log-odds ratio that has been adjusted for random imbalance of covariates. Data from a randomized clinical trial are used to compare results from the traditional maximum likelihood logistic method with those from the nonparametric logistic method. We examine treatment parameter estimates, corresponding standard errors, and significance levels in models with and without covariate adjustment. In addition, we discuss differences between unconditional population average treatment parameters and conditional subpopulation average treatment parameters. Additional features of the nonparametric method, including stratified (multicenter) and multivariate (multivisit) analyses, are illustrated. Extensions of this methodology to the proportional odds model are also made.

Issues for covariance analysis of dichotomous and ordered categorical data from randomized clinical trials and non-parametric strategies for addressing them.

Analysis of covariance is an effective method for addressing two considerations for randomized clinical trials. One is reduction of variance for estimates of treatment effects and thereby the production of narrower confidence intervals and more powerful statistical tests. The other is the clarification of the magnitude of treatment effects through adjustment of corresponding estimates for any random imbalances between the treatment groups with respect to the covariables. The statistical basis of covariance analysis can be either non-parametric, with reliance only on the randomization in the study design, or parametric through a statistical model for a postulated sampling process. For non-parametric methods, there are no formal assumptions for how a response variable is related to the covariables, but strong correlation between response and covariables is necessary for variance reduction. Computations for these methods are straightforward through the application of weighted least squares to fit linear models to the differences between treatment groups for the means of the response variable and the covariables jointly with a specification that has null values for the differences that correspond to the covariables. Moreover, such analysis is similarly applicable to dichotomous indicators, ranks or integers for ordered categories, and continuous measurements. Since non-parametric covariance analysis can have many forms, the ones which are planned for a clinical trial need careful specification in its protocol. A limitation of non-parametric analysis is that it does not directly address the magnitude of treatment effects within subgroups based on the covariables or the homogeneity of such effects. For this purpose, a statistical model is needed. When the response criterion is dichotomous or has ordered categories, such a model may have a non-linear nature which determines how covariance adjustment modifies results for treatment effects. Insight concerning such modifications can be gained through their evaluation relative to non-parametric counterparts. Such evaluation usually indicates that alternative ways to compare treatments for a response criterion with adjustment for a set of covariables mutually support the same conclusion about the strength of treatment effects. This robustness is noteworthy since the alternative methods for covariance analysis have substantially different rationales and assumptions. Since findings can differ in important ways across alternative choices for covariables (as opposed to methods for covariance adjustment), the critical consideration for studies with covariance analyses planned as the primary method for comparing treatments is the specification of the covariables in the protocol (or in an amendment or formal plan prior to any unmasking of the study.

Surgery for recurrent colon cancer: strategies for identifying resectable recurrence and success rates after resection. Eastern Cooperative Oncology Group, the North Central Cancer Treatment Group, and the Southwest Oncology Group.

BACKGROUND: Follow-up testing after surgery for colon cancer is recommended principally to identify resectable recurrences, but data on the efficacy of, outcomes of, and optimal strategies for this testing are limited. OBJECTIVES: To determine the relation between follow-up tests and salvage surgery, assess outcomes, and document surgical mortality. DESIGN: Retrospective cohort study. SETTING: A North American multi-institutional trial comparing postoperative chemotherapy plus follow-up with follow-up alone. PATIENTS: 1247 patients with resected stage II and stage III colon cancer. INTERVENTION: The protocol mandated follow-up testing that could be supplemented at the discretion of treating physicians. Indications of recurrent disease were documented. MEASUREMENTS: Recurrence, resectable recurrence, surgical mortality, and survival were studied. RESULTS: 548 patients had recurrence of colon cancer. Salvage surgery was attempted in 222 patients (41%). In 109 patients (20%), curative-intent surgery was done for hepatic recurrence (28 patients), pulmonary metastasis (20 patients), local recurrence (24 patients), or recurrence at other sites (37 patients). Most curative-intent surgical procedures were motivated by follow-up testing (36 patients), elevated carcinoembryonic antigen level (41 patients), or symptoms (27 patients). The median follow-up time after curative-intent surgery exceeded 5 years; the estimated 5-year disease-free survival rate was 23%. A solitary lesion was a favorable prognostic factor. The surgical mortality rate was 2%. Curative-intent resections were done in 15 patients with second primary colorectal cancer; 12 of these patients have survived disease-free. CONCLUSIONS: Second operations for colon cancer that are triggered by follow-up testing or symptoms are common and can result in long-term disease-free survival.

Effects of beam collimation on image quality.

PURPOSE: The purpose of this study was to determine the effect of three film-speed/collimator combinations on image quality, based on reviewer preference and diagnostic quality, based on caries detection. METHOD: Two hundred sixteen proximal surfaces were evaluated for the presence and severity of carious lesions on bitewing-simulated projections using D-speed film/circular, E-speed film/rectangular, and E-speed film/circular collimation. Matched films by model type were ranked, based on reviewer preference. Preference data were analyzed using Friedman's test, while the caries detection data were analyzed using a 3 x 3 x 3 x 6 ANOVA model and the kappa statistic. Variability components of the ANOVA were used to determine inter- and intra-rater reliability. RESULTS: Inter- and intra-rater reliability were 90.9 and 98.7%, respectively. Each of the film-speed/collimator combinations had average preference rankings that were significantly different from one another for each criteria (p < 0.001), with E-speed film/rectangular collimation consistently ranking highest and E-speed film/circular collimation consistently ranking lowest. There was excellent agreement in caries detection among the three film-speed/collimator combinations (kw = 0.92, kw = 0.94). CONCLUSION: Results from the subjective comparison indicated that E-speed film with rectangular collimation ranked highest for film resolution, overall appearance, and choice for caries diagnosis, while E-speed film with circular collimation ranked lowest. Caries diagnosis was comparable among the three film-speed/collimator combinations.

Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer.

PURPOSE: To determine the effectiveness of fluorouracil plus levamisole administered postoperatively to patients with resected stage II (Dukes' B2) colon cancer. PATIENTS AND METHODS: This randomized controlled clinical trial (INT-0035) was performed by National Cancer Institute-sponsored cancer clinical trials cooperative groups. Patients were assigned to observation only or to fluorouracil (450 mg/m2 intravenously [IV] daily for 5 days and, beginning at 28 days, weekly for 48 weeks) plus levamisole (50 mg orally three times daily for 3 days repeated every 2 weeks for 1 year). Cancer recurrence, survival, and treatment side effects were assessed. RESULTS: Three hundred eighteen eligible patients were analyzed with a median follow-up time of 7 years. Fluorouracil plus levamisole reduced the recurrence rate by 31%, although this trend was not statistically significant (P = .10). A total of 87 patients died: 43 on observation and 44 on fluorouracil plus levamisole. Disparity between effects on recurrence rate and overall survival is partially explained by a higher rate of non-colon cancer-related deaths on fluorouracil plus levamisole (15 v seven) and by the effects of salvage surgery with curative intent. Of seven patients with recurrence who were rendered disease-free by salvage surgery, six were on the observation arm. As was observed in patients treated with fluorouracil plus levamisole for stage III disease, toxicity was acceptable and compliance was excellent. CONCLUSION: Fluorouracil plus levamisole is tolerable and accepted as standard surgical adjuvant therapy for patients with stage III colon cancer, but the data from this study in stage II patients suggest a decreased relapse rate without a significant improvement in survival.

Phase II evaluation of low-dose continuous 5-fluorouracil and weekly cisplatin in advanced adenocarcinoma of the stomach. A Southwest Oncology Group study.

We have conducted a Phase II trial in patients with metastatic gastric cancer utilizing low-dose continuous infusion 5-fluorouracil (5FU) and weekly cisplatin (CDDP). The 5FU was administered at a dose of 200 mg/m2 per day by 24-hour continuous infusion via a permanent central venous catheter. The CDDP was administered at a dose of 20 mg/m2/week for the first 8 weeks, then every other week thereafter. Patients were evaluated for response every 8 weeks. There were 2 complete and 2 partial responses out of 39 eligible and evaluable patients for an overall response rate of 10% (95% CI = 3-24%). The primary toxicities were nausea, hyponatremia, and anemia. Overall, treatment was well tolerated. We conclude that, although the treatment is relatively well tolerated, the regimen has minimal activity in this disease and does not deserve further study.

Phase II study of 5-fluorouracil and folinic acid in the treatment of patients with advanced gastric cancer. A Southwest Oncology Group study.

BACKGROUND: The biochemical modulation of 5-fluorouracil (5-FU) by the reduced folate folinic acid (FA) in the treatment of patients with advanced gastric cancer was examined. METHODS: The Southwest Oncology Group performed parallel randomized Phase II trials of two schedules of 5-FU and FA in 80 patients with advanced gastric cancer. Of 76 analyzable patients, 36 were randomized to receive bolus FA (200 mg/m2, days 1-4) along with continuous infusion 5-FU (1000 mg/m2, days 1-4) and 40 were randomized to receive bolus FA (200 mg/m2, days 1-5) before the bolus 5-FU (375 mg/m2, days 1-5). RESULTS: There were three (8%) partial responses (95% confidence interval [CI] 2%-22%) on the continuous infusion arm. The bolus arm had two (5%) complete responses and six (15%) partial responses for an overall response rate of 20% (95% CI 9%-36%). The median duration of response was 4.6 months for the infusion patients and 16.6 months for the bolus patients. Survival was poor, with median survival of 5 months on both regimens. Gastrointestinal toxicity was substantial, with Grade 3 mucositis observed in 36% of patients on the continuous infusion regimen versus only 10% of patients on the bolus regimen. Grade 3 or higher hematologic toxicity occurred more often in the bolus arm than in the continuous infusion arm (28% vs. 14%, respectively). Two toxic deaths occurred, one related to sepsis the other secondary to coronary insufficiency. CONCLUSIONS: Biochemical modulation of 5-FU by FA using the dose and schedules tested has only modest activity in the treatment of advanced gastric cancer.