Cancer lung nutrition

Study objectives: To develop and validate a model for estimating the risk of lung cancer death in current and former smokers. The model is intended for use in analyzing a population of subjects who are undergoing lung cancer screening or receiving lung cancer chemoprevention, to determine whether the intervention has altered lung cancer mortality.

Design/setting/patients: Model derivation was based on analyses of the placebo arm of the Carotene and Retinol Efficacy Trial. Model validation was based on analyses of three other longitudinal cohorts.

Measurements: Observed and predicted number of deaths due to lung cancer.

Results: In internal validation, the model was highly concordant and well calibrated. In external validation, the model predictions were similar to what was observed in all of the validation analyses. The predicted and observed deaths within 6 years were very similar when assessed in the Johns Hopkins Hospital trial of chest radiography and sputum cytology screening (176 predicted, 184 observed, p = 0.53), the Memorial Sloan-Kettering Cancer Center trial of chest radiography and sputum cytology screening (108 predicted, 114 observed, p = 0.57), and the National Health and Nutrition Evaluation Survey part I (24 predicted, 21 observed, p = 0.52).

Conclusions: The number of lung cancer deaths in a population of current or former smokers can be accurately predicted, making model-based evaluations of prevention and early detection interventions a useful adjunct to definitive randomized trials. We illustrate this potential use with a small example.

Key words: Cancer screening; CT; logistic models; lung cancer; risk assessment

Abbreviations: CARET = Carotene and Retinol Efficacy Trial; JHH = Johns Hopkins Hospital; LDCT = low-dose CT; MSKCC = Memorial Sloan-Kettering Cancer Center. NHANES = National Health and Nutrition Evaluation Survey

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The newest hope for lung cancer screening, low-dose CT (LDCT), is being evaluated in a number of studies. Many of these studies, (1-3) such as the Early Lung Cancer Action Project, have annually screened current and former smokers with LDCT and tracked their outcomes, but have not included a contemporaneous control group. More recently, a large randomized trial called the National Lung Screening Trial has been launched, in which half of current and former smokers will be screened with LDCT, while the other half will serve as control subjects. (4)

It is generally accepted that the only valid end point for evaluations of cancer screening programs is cancer-specific mortality. (5) As such, most investigators agree that the randomized trial will produce a definitive estimate of the impact of screening, because it will allow the lung cancer mortality rate among individuals who are screened with LDCT to be directly compared with the lung cancer mortality rate of a similar group ("the controls") who are not screened with LDCT. Investigators disagree about studies that have not included a control group, in which stage at diagnosis and survival after diagnosis are the primary end points; in the context of a screening program, changes in these measures may not be predictive of changes in cancer-specific mortality, due to phenomena such as "lead time" and "length time" bias. (6)

What has not been considered is whether this "gold standard" outcome for screening evaluation--the lung cancer mortality rate--can be examined in the groups who have been screened, to determine if this rate is lower than it would have been in the absence of screening. To perform such a comparison would require that the lung cancer mortality rate that would have occurred in the absence of screening could be accurately anticipated. In this article, we describe a model that can be used to calculate the expected number of lung cancer deaths that will occur within a population of current and former smokers in the absence of screening or prevention intervention.

There is precedent for using nonrandomized comparisons to evaluate the impact of screening strategies. Investigators (7-9) concluded that the Papanicolou test reduced the cervical cancer mortality rate when rates of cervical cancer incidence and mortality were reduced after introduction of the test. However, in these studies, (7-9) the magnitude of the screening impact was very large. In contrast, investigators (10-11) concluded that newborn screening for neuroblastoma did not reduce mortality from the disease by comparing neuroblastoma mortality rates in populations that were screened to other populations that had not been screened. Lung cancer differs from these examples in that investigators seek to demonstrate a more modest impact than that demonstrated for the Papanicolou test or for colonoscopy. However, lung cancer is also unusual in that the major risk factors--cigarette smoking and age--have a very strong impact on risk, and the degree of exposure is easily obtained from an interview. (12)

MATERIALS AND METHODS

Our prediction model was derived on data collected from subjects enrolled in the Carotene and Retinol Efficacy Trial (CARET), a multicenter, randomized controlled study (13-14) that evaluated the impact of beta-carotene and vitamin A on lung cancer mortality. CARET enrolled two populations. There were 14,254 "heavy smokers" (men and women, aged 50 to 69 years), who had at least 20 pack-years of smoking exposure and were either current smokers or had quit within 6 years of enrollment. There were 4,060 "asbestos-exposed" men (aged 45 to 69 years, either current smokers or former smokers who quit within 15 years of enrollment), who had either radiologic evidence of asbestos exposure or a history of employment in a high-risk trade (primarily shipyard or construction work). All participants were randomized either to a placebo or to the intervention (30 mg/d beta-carotene and 25,000 IU/d retinyl palmitate). Enrollment in the pilot study began in 1985, full-scale recruitment began in 1988, and study accrual ended in September 1994. The intervention was stopped in January 1996 after preliminary results revealed definitive evidence of no benefit and substantial evidence of possible harm. (14)

The data from CARET are highly appropriate for deriving our model. They are rich in subjects and events, and the risk factors and outcomes were evaluated and recorded scrupulously. Moreover, the population of subjects in CARET are relevant to our purposes, in that they are drawn from six geographically diverse areas of the United States (Seattle WA, Portland OR, Irvine CA, Baltimore MD, New Haven CT, San Francisco CA), they consist only of volunteers in a clinical trial of cancer prevention, and they possess the smoking risks that make them strong candidates for lung cancer screening and prevention.

Our approach to model development and initial testing paralleled that which we used to develop a model of an individual's risk of having lung cancer diagnosed. (12) First, the data in CARET were divided into separate person-time periods. The beginning of each time period was defined by date of an encounter with a study coordinator (either initial or follow-up), and the end of the time period was defined either by the date of the outcome (death due to lung cancer) or by the date of a censored event (subsequent follow-up encounter, death due to another cause, end of the data). These person-time periods were then coded as either commencing within 1 year of study entry, or commencing after that point. The data were dichotomized in this manner to capture any risk attenuation that was initially present among study entrants due to their being asymptomatic at the time of enrollment.

Our validation involved subjects in the following three cohorts (Table 1): the National Health and Nutrition Evaluation Survey (NHANES) I (6); the Memorial Sloan-Kettering Cancer Center (MSKCC) randomized trial of chest radiograph and sputum cytology screening (15); and the Johns Hopkins Hospital (JHH) randomized trial of chest radiograph and sputum cytology screening. (16) These validation cohorts were comprised of individuals who were eligible for and elected to enroll in longitudinal health studies, making them well suited to our purposes. There were also some shortcomings to the use of these cohorts. The NHANES I cohort is small, and the subjects were not asked about asbestos exposure; we assumed in our analyses that none of the subjects had been exposed to asbestos. The MSKCC and JHH cohorts included male subjects only; moreover, all subjects were screened for lung cancer in the context of the study. Because it is widely accepted that the screening interventions in these studies did not alter the lung cancer mortality rates, we assumed that the lung cancer mortality rates in these studies were similar to rates that would have been observed in the absence of screening. (6,15,16)