Limitations and advantages of meta-analysis in clinical trials.
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Clinical Trials as Topic↗
Biomedical subjects
C K Redmond
Publications and source records attributed to C K Redmond.
Chromosomal aberrations and sister-chromatid exchanges in lymphocytes from coke oven workers.
To test whether coke oven workers, an occupational group known to be at increased cancer risk, manifest increased peripheral blood chromosomal aberration frequencies, we obtained samples from a group of 30 steelworker volunteers, who had worked several years at coke oven jobs. Exposure estimates were made using measurements of work place atmospheric coal tar pitch volatiles and work histories. No statistically significant positive regression of chromosomal aberrations on exposure estimates was found. The data from the coke oven workers were also compared with the obtained concurrently and employing precisely the same laboratory protocol from a group of male Brookhaven National Laboratory employees. The coke oven workers as a group were found to have statistically significantly elevated frequencies of chromatid aberrations and of sister-chromatid exchanges.
Aneuploidy↗
Serum level changes after administration of a pharmacologic dose of beta-carotene.
Results from a pilot study to assess the feasibility of conducting a full-scale lung-cancer-prevention trial using pharmacologic beta-carotene are reported. Participants in the study were randomized in a double-blind fashion to receive either 15 mg orally of beta-carotene or placebo daily. Findings for the first 300 men to complete 1 y on study are presented. After 10 mo of treatment, serum levels in the placebo group showed essentially no change whereas levels in the treated group increased almost 10-fold after 4 mo of treatment. The relationship between change in serum levels are evaluated in regard to body mass index, alcohol consumption, amount of smoking, lipids, and other variables. The results to date clearly indicate that substantial serum response can be achieved with only 15 mg/d and that with this dosage no skin discoloration or other toxicities are observed.
Alcohol Drinking↗
A multistage approach to the cohort analysis of lifetime lung cancer risk among steelworkers exposed to coke oven emissions.
A cohort analysis was performed to predict the lifetime lung cancer risk to a US or Canadian nonwhite male steelworker exposed to coke oven emissions. The procedure employed required that the lung cancer mortality (used for risk assessment) be estimated by addition of the excess to the background rates. The age-specific excess rates were obtained following selection of the proper excess risk function as implied by the multistage theory of carcinogenesis. A quantitative approach based on model fitting was used for selection of the excess risk function. The results show no evidence that coke oven emissions have a late stage carcinogenic effect. The indication that the agent acts as an initiator is moderate to weak. The number of carcinogenic stages involved was estimated to be four. Based on the assumption that exposure was set at a high concentration for 40 years with a starting age of 20 years, it was estimated that the lifetime risk through age 85+ years for a hypothetical US or Canadian nonwhite male oven worker could be as high as 0.40. This represents a 15-fold increase of the baseline risk.
Adult↗
Treatment of adult lower extremity lymphedema with the Wright linear pump: statistical analysis of a clinical trial.
Seventy-three adult lymphedema patients with 78 affected lower extremities were treated with the Wright Linear Pump. All patients were admitted for a 48-hour clinical trial. Comparison of circumferential limb measurements before and after a 48-hour treatment period using a repeated measures analysis of variance showed statistically significant improvement (p less than 0.00005). Although the improvement appeared to be somewhat more pronounced for men than for women, both sexes experienced an important reduction in leg circumference after therapy. Other factors such as age, etiology, previous use of the Jobst pump, or duration of lymphedema did not appear to influence the extent of improvement. These data clearly indicate that the Wright Linear Pump is an effective treatment for lower extremity lymphedema in adults.
Adolescent↗
Screening for geographic heterogeneity of disease rates: application to cancer incidence in Allegheny County, Pennsylvania, 1969-71.
A statistical technique for analyzing heterogeneity in rates proposed by Gail is potentially well-suited to the analysis of geographic patterns in disease incidence data. This was applied to 1969-71 cancer incidence in whites in 30 census tract aggregates within Allegheny County, Pennsylvania to ascertain its usefulness and to search for patterns. A product model, in which each area's risks are a constant multiple of one another across age groups, was found to adequately fit the observed data. The test for geographic heterogeneity indicated that 19 of 30 sex-site groupings manifested greater than chance variation across the county subunits, generally consistent with the number of outliers based on 95% confidence limits. Partitioning the heterogeneity in these sites by median income quintiles suggested a positive risk gradient with breast cancer (F) and negative risk gradients with rectal (M), pancreatic (F), lung (M), cervical (F), and bladder cancer (F). Percent foreign stock was positively associated with total cancer (M, F), colon (M, F), pancreatic (F), lung (M), and bladder cancer (M, F). The technique successfully demonstrated the accuracy of a product model, screened cancer sites meriting detailed study, and suggested several associations of median income and percent foreign stock with cancer risk.
Emigration and Immigration↗
Selection, follow-up, and analysis in the Coke Oven Study.
The current standard for exposure to coke oven emissions sets a permissible exposure of 150 micrograms benzene-soluble fraction of total particulate matter/m3. The major epidemiologic study that formed the basis for this standard including a review of the evidence of a dose-response relationship between exposure to coal tar pitch volatiles and lung cancer is reviewed. Particular attention was given to the selection of the cohort, follow-up procedures, and the evolution of the analysis.
Coal↗
Site-specific cancer mortality among workers involved in the production of high nickel alloys.
This report describes the cause-specific mortality patterns of 28 261 workers employed at 12 plants involved in the production of high nickel alloys during the late 1950s and 1960s and followed up to 31 December 1977. Findings for site-specific cancers that have previously been related to nickel exposures are: (1) Overall, no statistically significant increased risk has been observed for cancers of the lung, nasal sinuses, larynx or kidney. (2) When data were examined by occupational groupings, an excess risk of dying from cancers of the lung of about 25-50% for males employed in maintenance categories has been noted. It is unclear whether the greater risk is directly associated with nickel exposures, particularly since a similar excess is not found in other occupational groups where nickel exposures are also present. Two other cancer sites, liver and large intestine, not previously associated with nickel exposures in epidemiological studies, demonstrate a statistically significant standardized mortality ratio (SMR). The SMRs are 182 and 233 respectively, and observed increases in SMRs are found primarily among longer-term workers in the industry but are not concentrated in a particular work area or occupational category. No conclusion regarding a causal association with nickel has been drawn for these two sites at this time.
Adult↗
Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer. An NSABP update.
The current findings completely affirm the validity of our original observations indicating the appropriateness of grouping primary breast cancer patients into those with negative, 1 to 3, or greater than or equal to 4 positive nodes. Results, however, reveal that there is a risk in combining all patients with greater than or equal to 4 positive nodes into a single group. Since there was a 25% greater disease-free survival and an 18% greater survival in those with 4 to 6 than in those with greater than or equal to 13 positive axillary nodes, such a unification may provide misleading information regarding patient prognosis, as well as the worth of a therapeutic regimen when compared with another from a putatively similar patient population. Of particular interest were findings relating the conditional probability, i.e., the hazard rate, of a treatment failure or death each year during the 5-year period following operation to nodal involvement with tumor. Whereas the hazard rate for those with negative, or 1 to 3 positive nodes, was relatively low and constant, in those with greater than or equal to 4 positive nodes the risk in the early years was much greater, but by the fifth year it was similar to that occurring when 1-3 nodes were involved, and not much different from negative node patients. The same pattern existed whether 4 to 6 or greater than or equal to 13 nodes were positive. When the current findings are considered relative to other factors with predictive import, it is concluded that nodal status still remains the primary prognostic discriminant.
Axilla↗
Tumor size and regional lymph node metastasis in colorectal cancer. A preliminary analysis from the NSABP clinical trials.
This study explores the relationships between tumor size and regional lymph node involvement in patients with Dukes' B and C colorectal cancer in the randomized prospective clinical trials of the NSABP. Six-hundred and seventy patients with colon cancer and 236 patients with carcinoma of the rectum were available for analysis. Utilizing cumulative frequency distributions of tumor diameter and tumor volume, comparisons were carried out between Dukes' B and C lesions. The results indicate that there was no correlation between the longest diameter of the primary tumor and the status of regional lymph nodes for either colon or rectal cancer. Moreover, this lack of association was evident throughout the distribution. When tumor volume was analyzed, Dukes' B tumors proved to be consistently larger than Dukes' C lesions. This inverse relationship was statistically significant for carcinoma of the rectum. These findings underscore the unique biological behavior of colorectal cancer and emphasize the function of the current generation of randomized prospective trials in providing natural history information.
Clinical Trials as Topic↗
Relation of estrogen and/or progesterone receptor content of breast cancer to patient outcome following adjuvant chemotherapy.
In 1977 the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated a prospectively randomized clinical trial to evaluate the relative merits of 1-phenylalanine mustard and 5-fluorouracil (PF) with and without tamoxifen (T) as adjuvant therapy for patients with primary breast cancer and positive axillary nodes. A previous presentation of findings noted that there was a strong relationship between the outcome of those receiving PFT and the estrogen receptor (ER) and progesterone receptor (PR) content of their tumors. This report relates the outcome of the PF-treated patients in that trial with these tumor receptors. It indicates that the results observed following nonhormonal therapy (PF) are also related to tumor receptors. Both the disease-free survival (DFS) and survival (S) of women following PF therapy were influenced by the ER and PR content of their tumors. Subsequent to adjustment for other prognostic variables, the predictive influence of tumor ER persisted. Both the DFS (p = 0.0003) and the S (p = 0.00003) were significantly higher in those with greater than or equal to 10 fmol tumor ER than in those with less than 10 fmol ER. The PR significantly added to the predictive value of ER. Thus, this analysis is the first to demonstrate that having information on both ER and PR is important for predicting outcome of patients receiving adjuvant chemotherapy. The study does not provide information which correlates receptor status with the response of patients to adjuvant chemotherapy since there is no similar nonchemotherapy-treated group of patients in the trial. The findings continue to emphasize that there is a heterogeneity in outcome of breast cancer patients to adjuvant chemotherapy which is related to an increasing number of host and tumor variables. For proper assessment of overall results, it is essential that analyses employ tests for interaction to indicate homogeneity or heterogeneity of patient subsets and that adjustments be made for imbalances in tumor ER and PR as well as in other prognostic factors.
Antineoplastic Combined Chemotherapy Protocols↗
Breast cancer estrogen and progesterone receptor values: their distribution, degree of concordance, and relation to number of positive axillary nodes.
Increasing evidence indicates the importance of ascertaining the quantitative estrogen receptor (ER) and progesterone receptor (PR) content (in femtomoles per milligram cytosol protein) of primary breast cancers. Those values obtained from the tumors of 1,887 patients participating in National Surgical Adjuvant Breast and Bowel Project protocol B-09 have been analyzed to define (1) the distribution of tumor ER or PR according to patient age, (2) the distribution of tumor PR within a specific ER interval, and (3) the concordance of tumor ER and PR levels. The present findings indicate how predictive the knowledge of the amount of one receptor (e.g., ER) may be for estimating the amount of the other (PR), when the latter is unknown.
Age Factors↗
Cancer mortality among coke oven workers.
The OSHA standard for coke oven emissions, which went into effect in January 1977, sets a permissible exposure limit to coke oven emissions of 150 micrograms/m3 benzene-soluble fraction of total particulate matter (BSFTPM). Review of the epidemiologic evidence for the standard indicates an excess relative risk for lung cancer as high as 16-fold in topside coke oven workers with 15 years of exposure or more. There is also evidence for a consistent dose-response relationship in lung cancer mortality when duration and location of employment at the coke ovens are considered. Dose-response models fitted to these same data indicate that, while excess risks may still occur under the OSHA standard, the predicted levels of increased relative risk would be about 30-50% if a linear dose-response model is assumed and 3-7% if a quadratic model is assumed. Lung cancer mortality data for other steelworkers suggest the predicted excess risk has probably been somewhat overestimated, but lack of information on important confounding factors limits further dose-response analysis.
Coal↗
Impact of randomized clinical trials on therapy of primary breast cancer: the NSABP overview.
The history of treatment for early breast cancer, particularly as it relates to the most recent calendar decade, exemplifies the contribution that can be made to resolving therapeutic controversies by well-designed prospective randomized clinical trials (RCTs). In this article we provide an overview of the breast cancer clinical trials that have been conducted by the National Surgical Adjuvant Project for Breast and Bowel Cancers (NSABP) since 1971. These trials have had a strong impact in changing the clinical management of breast cancer over the past decade. Emphasis will be given to those aspects of the studies that demonstrate the advantages and/or necessity for RCTs to evaluate alternative therapeutic approaches to the management of breast cancer.
Antineoplastic Agents↗
The relationship between the geographic distribution of lung cancer incidence and cigarette smoking in Allegheny County, Pennsylvania.
The results of the Third National Cancer Survey have shown substantial variations in lung cancer incidence rates for white males within Allegheny County, Pennsylvania. To explain these differences, two areas showing over a twofold difference in the 1970 age-adjusted incidence rates (127.7 compared to 59.0 per 100,00) were studied in greater detail. Estimates of smoking experience by age were determined in the two areas by survey sampling methods of white males 35 years of age and older. The results show the high risk area had a significantly greater proportion of males currently smoking and who had ever smoked cigarettes compared to the low risk area. Males in the high risk area also began smoking over four years earlier, and proportionally fewer men smoked filter cigarettes. Calculations of Lung cancer risk based on these results and a model of risk from the prospective and retrospective studies showed that almost all of the observed difference in risk between areas was attributable to cigarettes.
Adult↗
An overview of the breast protocols of NSAPB.
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Antineoplastic Agents↗
Sensitive population subsets in relation to effects of low doses.
This paper presents an overview of current knowledge relative to identification and quantification of sensitive population subgroups, utilization of sensitive subgroups for studying low dose-effects and issues in formulating environmental policies from information on sensitive subsets of the population. General factors that contribute to sensitivity are developmental periods, genetic conditions, nutritional deficiencies, predisposing diseases and personal habits. An illustration of age-related sensitivity to radiation is given, which shows that one would need to examine ten times the number of metaphase cells from individuals age 25 as from those age 55 to obtain equivalent statistical precision in identifying increased numbers of radiation induced aberrations. Hence, knowledge of susceptible subsets is useful for study design and analysis. Important concerns noted in proposing standards include: whether to protect the entire population when only a small fraction is at increased risk; what emphasis should be placed on alteration of the predisposing factors, e.g., nutrition; and how to acquire the additional protection for sensitive groups in standards based on the general population.
Adult↗
Correlation of estrogen receptor and pathologic characteristics of invasive breast cancer.
Estrogen receptor (ER) status was correlated with a large number of pathological and clinical characteristics of 178 invasive breast cancers. Positive ER was found to be significantly associated with high nuclear and low histologic grades, absence of tumor necrosis, presence of marked tumor elastosis, and older patients. These pathologic parameters enumerated are either directly or indirectly related to tumor differentiation suggesting that ER represents another index of this latter. Multivariate analyses disclosed that both age and tumor differentiation are associated with the ER status. Well-differentiated tumors were more frequently ER+ in older women. Inclusion of an estimate of tumor necrosis as well as patient age appears to allow for further discrimination of ER status in poorly differentiated lesions. Considerations relative to ER and tumor differentiation provide a possible explanation for the dichotomy of response to adjuvant chemotherapy observed in pre and postmenopausal women.
Adult↗