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.

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.

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.

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.

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.

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.

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 study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study.

PURPOSE: A variety of fluorinated pyrimidine-based regimens for the treatment of disseminated colorectal cancer have been presented in the medical literature. The Southwest Oncology Group designed a screening trial of seven regimens of fluorouracil (5-FU) to assess efficacy and toxicity afforded by biochemical modulation or schedule variations. PATIENTS AND METHODS: Six hundred twenty patients were entered into this trial between August 1989 and January 1993. Eligible patients were classified as having recurrent or disseminated disease that was measurable or nonmeasurable. All eligible patients were evaluated for toxicity and survival; patients with measurable disease were evaluated for response according to standard criteria. RESULTS: No regimen achieved a higher response rate than single-agent bolus 5-FU. Eighty-four percent of patients have been monitored until death. The median survival time for the entire cohort is 14 months. Survival hazards ratios showed a positive trend in favor of the unmodulated infusion regimens, while high-grade toxicities occurred more frequently in the 5-FU bolus arms. The major high-grade toxicities were granulocytopenia and diarrhea. CONCLUSION: In this trial, no regimen provided substantial improvement relative to 5-FU bolus or single-agent therapy for either response or survival in the treatment of disseminated colorectal cancer. The single-agent infusion regimens demonstrated the most encouraging results with a favorable toxicity profile and a 2-month longer survival duration than 5-FU bolus therapy.

Adjuvant continuous infusion 5-FU, whole-abdominal radiation, and tumor bed boost in high-risk stage III colon carcinoma: a Southwest Oncology Group Pilot study.

PURPOSE: Results of a combined modality adjuvant pilot program of low-dose continuous-infusion 5-fluorouracil, whole-abdominal radiation, and tumor bed boost in patients with colon cancer with involved nodes and serosal involvement are presented. METHODS AND MATERIALS: Forty-one eligible patients with completely resected T3N1-2M0 colon cancer (modified Astler-Coller C2) were treated with 5-fluorouracil (5-FU) at a dose of 200 mg/m2/day by continuous infusion and 30 Gy of concomitant whole-abdominal radiation in 1 Gy fractions. An additional 16 Gy boost to the tumor bed was administered in 1.6 Gy fractions. After completion of combined modality treatment and a 21-day rest period, patients received 4 days of 5-FU at a dose of 1000 mg/m2 by continuous infusion every 28 days for nine cycles. RESULTS: Five-year disease-free and overall survival estimates were 58 and 67%, respectively, for all T3N1-2 patients. Five-year disease-free and overall survival estimates for the 19 patients with four or fewer nodes were both 61%. Five-year disease-free survival and overall survival estimates for the 20 patients with more than four involved nodes were 55% and 74%, respectively (the exact number of involved nodes were unknown for two patients). Disease-free and overall survival estimates for patients treated with 5-FU and radiation compare favorably to the 5-FU plus levamisole arm of the intergroup adjuvant colon study (Int 0035/SWOG 8591) in patients with more than four positive nodes where the 5-year disease-free and overall survival estimates were 35% and 39%, respectively. Disease-free and overall survival estimates for patients with four or fewer nodes in the 5-FU plus levamisole arm of the intergroup study were 64 and 68%, which is not markedly different from results obtained with radiation and 5-FU in the current study. There were no treatment-related fatalities. Seventeen percent of patients had severe and 7% had life-threatening toxicity of any kind. One patient had an acute partial bowel obstruction and two patients had chronic low grade enteritis. CONCLUSION: Continuous infusion 5-FU and whole-abdominal radiation with tumor bed boost should be further investigated in a larger trial of T3N1-2 colon cancer.

Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report.

OBJECTIVE: To determine the effectiveness of two adjuvant therapy regimens in improving surgical cure rates in stage III (Dukes stage C) colon cancer. DESIGN: Randomized, concurrently controlled clinical trial. SETTING: Major cancer centers, universities, and community clinics affiliated with the North Cancer Treatment Group, the Southwest Oncology Group, and the Eastern Cooperative Oncology Group. PATIENTS: Those who had had curative-intent resections of stage III colon cancer in the previous 1 to 5 weeks. INTERVENTION: Patients were assigned to observation only, to levamisole alone (50 mg orally three times/d for 3 days, repeated every 2 weeks for 1 year), or to this regimen of levamisole plus fluorouracil (450 mg/m2 body surface area intravenously daily for 5 days and then, beginning at 28 days, weekly for 48 weeks). MEASUREMENTS: Rates of cancer recurrence and death. Early- and late-treatment side effects. RESULTS: With all 929 eligible patients able to be followed for 5 years or more (median follow-up, 6.5 years), fluorouracil plus levamisole reduced the recurrence rate by 40% (P < 0.0001) and the death rate by 33% (P = 0.0007). Levamisole reduced the recurrence rate by only 2% and the death rate by only 6%. With few exceptions, toxicity was mild and patient compliance was excellent. No evidence of late side effects was seen. CONCLUSION: Fluorouracil plus levamisole is tolerable adjuvant therapy to surgery; it has been confirmed to substantially increase cure rates for patients with high-risk (stage III) colon cancer. It should be considered standard treatment for all such patients not entered into clinical trials.

Phase II trial of dimethyltriazenoimidazole carboxamide in patients with metastatic carcinoid. A Southwest Oncology Group study.

BACKGROUND: The use of chemotherapy in patients with metastatic carcinoid tumors has been of limited value, and investigation of new agents is necessary. Previous reports have suggested that dimethyltriazenoimidazole carboxamide (DTIC) may have antitumor activity. METHODS: A Phase II trial to investigate the clinical response rate to DTIC in patients with metastatic carcinoid tumors was performed. DTIC was administered at low (650 mg/m2) or high (850 mg/m2) doses every 28 days. RESULTS: Sixty-three patients were entered into the study, and 56 were evaluable for toxicity and response. Toxicity was moderate, with the most common side effect being nausea and vomiting (88%). Nine patients (16%; 95% confidence interval, 8-28%) had partial responses, 5 of 25 receiving 850 mg/m2 and 4 of 31 receiving 650 mg/m2 of DTIC. Median survival time of all patients was 20 months. CONCLUSIONS: DTIC has minimal activity in patients with metastatic carcinoid tumors.

Treatment of advanced colorectal carcinoma with 5-fluorouracil, leucovorin and Roferon-A: a Southwest Oncology Study Group Study.

Based upon prior data suggesting that alpha-interferon possesses chemomodulatory activity, a pilot study was conducted in which patients with advanced colorectal carcinoma were treated with 5-fluorouracil (5-FU), leucovorin (LV) and Roferon-A. Treatment consisted of LV 20 mg/m2 i.v. push followed by 5-FU, 425 mg/m2 i.v. push daily for 5 days every 4 weeks for 2 cycles, then every 5 weeks; Roferon-A 9 million units subcutaneously was given three times weekly every week. Forty-six eligible patients with bidimensionally measurable disease who had received no prior chemotherapy for advanced disease were treated with this regimen. The most frequent toxicity was leukopenia with 80% of patients experiencing some degree of leukopenia and the most severe toxicity was granulocytopenia with 46% of patients experiencing granulocyte counts < 1,000/mm3. Among the 46 eligible patients, the objective response rate was 13% (95% confidence interval, 5-26%). Thirty-five of the 46 patients have died with a median survival of 17 months. This regimen has significant toxicity and insufficient activity against advanced colorectal carcinoma to warrant further trials.

Hepatoma/merbarone. A Southwest Oncology Group study.

Sixteen eligible patients with hepatocellular carcinoma, previously untreated, received merbarone 1000 mg/m2/d for five consecutive days every 21 days. No complete or partial response to treatment was obtained. Seven patients had grade 4 granulocytopenia. One patient died with renal failure. Merbarone in this dose and schedule was ineffective in the treatment of hepatocellular carcinoma.