Brenda Brewer

Results of the Two Incidence Screenings in the National Lung Screening Trial

BACKGROUND The National Lung Screening Trial was conducted to determine whether three annual screenings (rounds T0, T1, and T2) with low-dose helical computed tomography (CT), as compared with chest radiography, could reduce mortality from lung cancer. We present detailed findings from the first two incidence screenings (rounds T1 and T2). METHODS We evaluated the rate of adherence of the participants to the screening protocol, the results of screening and downstream diagnostic tests, features of the lung-cancer cases, and first-line treatments, and we estimated the performance characteristics of both screening methods. RESULTS At the T1 and T2 rounds, positive screening results were observed in 27.9% and 16.8% of participants in the low-dose CT group and in 6.2% and 5.0% of participants in the radiography group, respectively. In the low-dose CT group, the sensitivity was 94.4%, the specificity was 72.6%, the positive predictive value was 2.4%, and the negative predictive value was 99.9% at T1; at T2, the positive predictive value increased to 5.2%. In the radiography group, the sensitivity was 59.6%, the specificity was 94.1%, the positive predictive value was 4.4%, and the negative predictive value was 99.8% at T1; both the sensitivity and the positive predictive value increased at T2. Among lung cancers of known stage, 87 (47.5%) were stage IA and 57 (31.1%) were stage III or IV in the low-dose CT group at T1; in the radiography group, 31 (23.5%) were stage IA and 78 (59.1%) were stage III or IV at T1. These differences in stage distribution between groups persisted at T2. CONCLUSIONS Low-dose CT was more sensitive in detecting early-stage lung cancers, but its measured positive predictive value was lower than that of radiography. As compared with radiography, the two annual incidence screenings with low-dose CT resulted in a decrease in the number of advanced-stage cancers diagnosed and an increase in the number of early-stage lung cancers diagnosed. (Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385.).

The Polyp Prevention Trial–Continued Follow-up Study: No Effect of a Low-Fat, High-Fiber, High-Fruit, and -Vegetable Diet on Adenoma Recurrence Eight Years after Randomization

The Polyp Prevention Trial (PPT) was a multicenter randomized clinical trial to evaluate the effects of a high-fiber (18 g/1,000 kcal), high-fruit and -vegetable (3.5 servings/1,000 kcal), and low-fat (20% of total energy) diet on the recurrence of adenomatous polyps in the large bowel over a period of 4 years. Although intervention participants reported a significantly reduced intake of dietary fat, and increased fiber, fruit, and vegetable intakes, their risk of recurrent adenomas was not significantly different from that of the controls. Since the PPT intervention lasted only 4 years, it is possible that participants need to be followed for a longer period of time before treatment differences in adenoma recurrence emerge, particularly if diet affects early events in the neoplastic process. The PPT-Continued Follow-up Study (PPT-CFS) was a post-intervention observation of PPT participants for an additional 4 years from the completion of the trial. Of the 1,905 PPT participants, 1,192 consented to participate in the PPT-CFS and confirmed colonoscopy reports were obtained on 801 participants. The mean time between the main trial end point colonoscopy and the first colonoscopy in the PPT-CFS was 3.94 years (intervention group) and 3.87 years (control group). The baseline characteristics of 405 intervention participants and 396 control participants in the PPT-CFS were quite similar. Even though the intervention group participants increased their fat intake and decreased their intakes of fiber, fruits, and vegetables during the PPT-CFS, they did not go back to their prerandomization baseline diet (P < 0.001 from paired t tests) and intake for each of the three dietary goals was still significantly different from that in the controls during the PPT-CFS (P < 0.001 from t tests). As the CFS participants are a subset of the people in the PPT study, the nonparticipants might not be missing completely at random. Therefore, a multiple imputation method was used to adjust for potential selection bias. The relative risk (95% confidence intervals) of recurrent adenoma in the intervention group compared with the control group was 0.98 (0.88-1.09). There were no significant intervention-control group differences in the relative risk for recurrence of an advanced adenoma (1.06; 0.81-1.39) or multiple adenomas (0.92; 0.77-1.10). We also used a multiple imputation method to examine the cumulative recurrence of adenomas through the end of the PPT-CFS: the intervention-control relative risk (95% confidence intervals) for any adenoma recurrence was 1.04 (0.98-1.09). This study failed to show any effect of a low-fat, high-fiber, high-fruit and -vegetable eating pattern on adenoma recurrence even with 8 years of follow-up. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1745–52)

Carotenoids, vitamin A and risk of adenomatous polyp recurrence in the polyp prevention trial.

One trial reported beta‐carotene supplementation was protective of adenomatous polyp recurrence in nonsmokers. We now examine the relation of serum and dietary carotenoids and vitamin A to adenomatous polyp recurrence in a subcohort of 834 participants in a low fat, high fiber, high fruit and vegetable dietary intervention, the Polyp Prevention Trial. Multivariate odds ratio (OR) and 95% confidence intervals (CI) of polyp recurrence were obtained using baseline or the average (first 3 years of the trial) carotenoid and vitamin A values after adjustment for covariates. Compared to the lowest quartile of baseline alpha‐carotene concentrations, the OR of multiple polyp recurrence for the highest quartile was 0.55 (95% CI = 0.30–0.99) and the OR of right‐sided recurrence was 0.60 (95% CI = 0.37–0.95). Baseline dietary intakes of alpha‐carotene and vitamin A from food with/without supplements were inversely associated with any recurrence (pfor linear trend = 0.03‐ alpha‐carotene; p = 0.004 and p = 0.007 ‐intakes of vitamin A). Compared to the lowest quartile of averaged beta‐carotene concentrations, the OR of multiple adenomas for the highest quartile was 0.40 (95% CI = 0.22–0.75) with an inverse trend (p = 0.02). The risk was inversely related to averaged: alpha‐carotene concentrations and right‐sided polyps; alpha‐carotene intake and recurrence of any, multiple and right‐sided polyps; beta‐carotene intake and multiple adenoma recurrence; vitamin A from food (with supplements) and each adverse endpoint. Thus, alpha‐carotene and vitamin A may protect against recurrence in nonsmokers and nondrinkers or be indicative of compliance or another healthy lifestyle factor that reduces risk.

Does nutritionist review of a self-administered food frequency questionnaire improve data quality?

OBJECTIVE This study sought to evaluate the benefit of utilizing a nutritionist review of a self-administered food frequency questionnaire (FFQ), to determine whether accuracy could be improved beyond that produced by the self-administered questionnaire alone. DESIGN Participants randomized into a dietary intervention trial completed both a FFQ and a 4-day food record (FR) at baseline before entry into the intervention. The FFQ was self-administered, photocopied and then reviewed by a nutritionist who used additional probes to help complete the questionnaire. Both the versions before nutritionist review and after nutritionist review - were individually compared on specific nutrients to the FR by means, correlations and per cent agreement into quintiles. SETTINGS AND SUBJECTS Three hundred and twenty-four people, a subset of participants from the Polyp Prevention Trial - a randomized controlled trial examining the effect of a low-fat, high-fibre, high fruit and vegetable dietary pattern on the recurrence of adenomatous polyps - were recruited from clinical centres at the University of Utah, University of Buffalo, Memorial Sloan Kettering Cancer Center in New York and Kaiser Permanente Medical Program in Oakland. RESULTS Reviewing the FFQ increased correlations with the FR for every nutrient, and per cent agreement into quintiles for all nutrients except calcium. Energy was underestimated in both versions of the FFQ but to a lesser degree in the version with review. CONCLUSIONS One must further evaluate whether the increases seen with nutritionist review of the FFQ will enhance our ability to predict diet-disease relationships and whether it is cost-effective when participant burden and money spent utilizing trained personnel are considered.

Does Nonsteroidal Anti-inflammatory Drug Use Modify the Effect of a Low-Fat, High-Fiber Diet on Recurrence of Colorectal Adenomas?

The Polyp Prevention Trial was designed to evaluate the effects of a high-fiber (18 g/1,000 kcal), high-fruit and -vegetable (3.5 servings/1,000 kcal), low-fat (20% energy) diet on recurrence of adenomatous polyps. Participants ≥35 years of age, with histologically confirmed colorectal adenoma(s) removed in the prior 6 months, were randomized to the intervention or control group. Demographic, dietary, and clinical information, including use of nonsteroidal anti-inflammatory drugs (NSAID), was collected at baseline and four annual visits. Adenoma recurrence was found in 754 of 1,905 participants and was not significantly different between groups. NSAID use was associated with a significant reduction in recurrence [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.63-0.95]. In this analysis, NSAIDs modified the association between the intervention and recurrence at baseline (P = 0.02) and throughout the trial (P = 0.008). Among participants who did not use NSAIDs, the intervention was in the protective direction but did not achieve statistical significance (OR, 0.87; 95% CI, 0.69-1.09). The intervention was protective among males who did not use NSAIDs at baseline (OR, 0.71; 95% CI, 0.54-0.94), but not among NSAIDs users (OR, 1.09; 95% CI, 0.74-1.62). For females, corresponding OR estimates were 1.28 (95% CI, 0.86-1.90) and 2.30 (95% CI, 1.24-4.27), respectively. The protective association observed for NSAID use was stronger among control (OR, 0.63; 95% CI, 0.47-0.84) than for intervention group participants (OR, 0.97; 95% CI, 0.74-1.28). These results should be interpreted cautiously given that they may have arisen by chance in the course of examining multiple associations and Polyp Prevention Trial study participants were not randomly assigned to both dietary intervention and NSAID use. Nevertheless, our results suggest that adopting a low-fat, high-fiber diet rich in fruits and vegetables may lower the risk of colorectal adenoma recurrence among individuals who do not regularly use NSAIDs.

The Polyp Prevention Trial

Abstract The Polyp Prevention Trial (PPT) is a randomized clinical trial sponsored by the National Cancer Institute. National Institutes of Health, that tests the relationship between diet and the formation of large bowel adenomatous polyps, the precursor lesion for most large bowel cancers. Approximately 2000 participants from 8 Clinical Centers have been randomized into the trial. Half were assigned to the intervention group and asked to adopt a low-fat (20% of calories from fat), high-fiber (18grams/1000kcal), high fruit and vegetable (5 to 8 daily servings) eating plan. Numerous epidemiological studies suggest that these dietary factors may be protective for large bowel cancer. The remaining participants were assigned to the control group, maintaining their usual diet. Registered dietitians play a central and critical role in the PPT. The 4-year intervention program is delivered solely by RDs. The success of the intervention depends to a great degree on the abilities of these nutritionists to deliver the program effectively as well as to help participants sustain a high level of motivation for making long-term dietary changes. In addition, RDs at both the Coordinating Center and at the Clinical Centers play a vital role in ensuring standardization of the delivery and documentation of the intervention program. RDs also have the primary responsibility for administering the baseline and annual dietary assessments and for assuring quality and standardization of dietary assessment activities. The Polyp Prevention Trial provides opportunities not available to RDs working in typical clinical settings. For example, the study design allows for approximately 50 hours of in-person counseling for each participant along with resources to assist participants in making long-term changes. The PPT also presents unique challenges to nutritionists in their multiple roles of providing nutrition education and behavioral counseling; administering dietary assessments; maintaining objectivity and standardization; and performing administrative, organizational, and managerial activities.

Development and Validation of the Cholesterol-Saturated Fat Index (CSI) Scorecard: A Dietary Self-Monitoring Tool

OBJECTIVE The Cholesterol-Saturated Fat Index (CSI) Scorecard was developed and tested as a self-monitoring tool for patients consuming a cholesterol-lowering diet. SUBJECTS/DESIGN Twelve nutritionists used the CSI Scorecard to estimate the CSI score of the same five food records. Subsequently, using a revised tool, 12 subjects with hypercholesterolemia estimated the CSI score of their 4-day food records and 11 participated in evaluation meetings. STATISTICAL ANALYSES Two-tailed, one-sample t tests and the Spearman rho correlation test were used, respectively, to compare CSI Scorecard estimates of nutritionists and participants to CSI scores obtained from computer calculations. RESULTS The CSI scores estimated by the nutritionists were close to the computed scores at the 25th and 75th food record percentiles. The correlation of the estimated CSI scores of participants to the computed scores was rs = .8 (P < .05). APPLICATION The CSI Scorecard is a new, simple, quick, and accurate dietary self-monitoring tool patients can use in research centers and primary care settings. By numerically illustrating the saturated fat and cholesterol content of foods, the CSI Scorecard facilitates dietary self-monitoring and, thus, self-efficacy in the adoption and maintenance of a cholesterol-lowering dietary pattern.

Did death certificates and a death review process agree on lung cancer cause of death in the National Lung Screening Trial

Background/aims: Randomized controlled trials frequently use death review committees to assign a cause of death rather than relying on cause of death information from death certificates. The National Lung Screening Trial, a randomized controlled trial of lung cancer screening with low-dose computed tomography versus chest X-ray for heavy and/or long-term smokers ages 55–74 years at enrollment, used a committee blinded to arm assignment for a subset of deaths to determine whether cause of death was due to lung cancer. Methods: Deaths were selected for review using a pre-determined computerized algorithm. The algorithm, which considered cancers diagnosed during the trial, causes and significant conditions listed on the death certificate, and the underlying cause of death derived from death certificate information by trained nosologists, selected deaths that were most likely to represent a death due to lung cancer (either directly or indirectly) and deaths that might have been erroneously assigned lung cancer as the cause of death. The algorithm also selected deaths that might be due to adverse events of diagnostic evaluation for lung cancer. Using the review cause of death as the gold standard and lung cancer cause of death as the outcome of interest (dichotomized as lung cancer versus not lung cancer), we calculated performance measures of the death certificate cause of death. We also recalculated the trial primary endpoint using the death certificate cause of death. Results: In all, 1642 deaths were reviewed and assigned a cause of death (42% of the 3877 National Lung Screening Trial deaths). Sensitivity of death certificate cause of death was 91%; specificity, 97%; positive predictive value, 98%; and negative predictive value, 89%. About 40% of the deaths reclassified to lung cancer cause of death had a death certificate cause of death of a neoplasm other than lung. Using the death certificate cause of death, the lung cancer mortality reduction was 18% (95% confidence interval: 4.2–25.0), as compared with the published finding of 20% (95% confidence interval: 6.7–26.7). Conclusion: Death review may not be necessary for primary-outcome analyses in lung cancer screening trials. If deemed necessary, researchers should strive to streamline the death review process as much as possible.