Active follow-up versus passive linkage with cancer registries for case ascertainment in a cohort.

BACKGROUND: Ascertaining incident cancers is a critical component of cancer-focused epidemiologic cohorts and of cancer prevention trials. Potential methods: for cancer case ascertainment include active follow-up and passive linkage with state cancer registries. Here we compare the two approaches in a large cancer screening trial. METHODS: The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial enrolled 154,955 subjects at ten U.S. centers and followed them for all-cancer incidence. Cancers were ascertained by an active follow-up process involving annual questionnaires, retrieval of records and medical record abstracting to ascertain and confirm cancers. For a subset of centers, linkage with state cancer registries was also performed. We assessed the agreement of the two methods in ascertaining incident cancers from 1993 to 2009 in 80,083 subjects from six PLCO centers where cancers were ascertained both by active follow-up and through linkages with 14 state registries. RESULTS: The ratio (times 100) of confirmed cases ascertained by registry linkage compared to active follow-up was 96.4 (95% CI: 95.1-98.2). Of cancers ascertained by either method, 86.6% and 83.5% were identified by active follow-up and by registry linkage, respectively. Of cancers missed by active follow-up, 30% were after subjects were lost to follow-up and 16% were reported but could not be confirmed. Of cancers missed by the registries, 27% were not sent to the state registry of the subject's current address at the time of linkage. CONCLUSION: Linkage with state registries identified a similar number of cancers as active follow-up and can be a cost-effective method to ascertain incident cancers in a large cohort.

Evidence of a healthy volunteer effect in the prostate, lung, colorectal, and ovarian cancer screening trial.

Volunteers for prevention or screening trials are generally healthier and have lower mortality than the general population. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) is an ongoing, multicenter, randomized trial that randomized 155,000 men and women aged 55-74 years to a screening or control arm between 1993 and 2001. The authors compared demographics, mortality rates, and cancer incidence and survival rates of PLCO subjects during the early phase of the trial with those of the US population. Incidence and mortality from PLCO cancers (prostate, lung, colorectal, and ovarian) were excluded because they are the subject of the ongoing trial. Standardized mortality ratios for all-cause mortality were 46 for men, 38 for women, and 43 overall (100 = standard). Cause-specific standardized mortality ratios were 56 for cancer, 37 for cardiovascular disease, and 34 for both respiratory and digestive diseases. Standardized mortality ratios for all-cause mortality increased with time on study from 31 at year 1 to 48 at year 7. Adjusting the PLCO population to a standardized demographic distribution would increase the standardized mortality ratio only modestly to 54 for women and 55 for men. Standardized incidence ratios for all cancer were 84 in women and 73 in men, with a large range of standardized incidence ratios observed for specific cancers.

Complex ovarian cysts in postmenopausal women are not associated with ovarian cancer risk factors: preliminary data from the prostate, lung, colon, and ovarian cancer screening trial.

OBJECTIVE: We assessed whether asymptomatic ovarian abnormalities detected on ultrasonography in postmenopausal women are precursors to ovarian cancer. STUDY DESIGN: We compared the transvaginal ultrasonographic findings from the initial examination of 20,000 postmenopausal women enrolled to date in an ongoing randomized trial of cancer screening with data on the established risk factors for ovarian cancer obtained from self-administered questionnaires. We distinguished cysts with the suggestive characteristic(s) of a septum, a solid component, or an irregular or thick wall ("complex cysts") from simple sonolucent cysts with none of those features. RESULTS: High parity, a strong ovarian cancer protective factor, was negatively associated with complex cysts (odds ratio for > or =5 births vs no births, 0.72; 95% confidence interval, 0.53-0.97), but long-term oral contraceptive use, another strong ovarian cancer protective factor, was not associated with complex cysts (odds ratio, 0.96; 95% confidence interval, 0.76-1.20). A family history of ovarian cancer or multiple breast cancers, a strong risk factor for cancer, was not associated with complex cysts (odds ratio, 0.99; 95% confidence interval, 0.68-1.44). Other abnormalities found on ultrasonography (including simple cysts, bilateral cysts, or all abnormalities combined) also did not share the established risk factors for ovarian malignancy. We did not identify any combination of features of abnormalities (septum, echogenicity, size, or papillary projections) that manifested the cancer risk factor profile. CONCLUSIONS: Although a very small proportion of the clinically silent ovarian abnormalities found on ultrasonography are determined to be ovarian cancers, the remaining complex cysts and other clinically suspicious abnormalities do not appear to be the immediate precursors of ovarian cancer. The eventual identification of such precursors will yield opportunities for earlier diagnosis, screening of high-risk groups, and better understanding of the cause of this often lethal malignancy.

Complex ovarian cysts in postmenopausal women are not associated with ovarian cancer risk factors. Preliminary data from the plco cancer screening trial.

PURPOSE: We assessed whether ovarian abnormalities detected on ultrasound in postmenopausal women are precursors to ovarian cancer.METHODS: We compared the transvaginal ultrasound findings from the initial examination of twenty thousand postmenopausal women enrolled to date in an ongoing randomized trial of cancer screening to data on the established risk factors for ovarian cancer obtained from self-administered questionnaires. We distinguished cysts with the suspicious characteristics of a septum, solid component, irregular or thick wall ("complex cysts") from simple sonolucent cysts with none of those features.RESULTS: High parity, protective for cancer, was negatively associated with complex cysts (Odds Ratio ["OR"] for five or more births versus no births = 0.72, 95% CI = 0.53-0.97), but long-term oral contraceptive use was not (OR = 0.96, 95% CI = 0.76-1.20). A family history of ovarian cancer or multiple breast cancers, a strong risk factor for cancer, was not associated with complex cysts (OR = 0.99, 95% CI = 0.68-1.44). Other abnormalities found on ultrasound (including simple cysts, bilateral cysts, or all abnormalities combined) also did not share the established risk factors for ovarian malignancy. We formed no combination of features of abnormalities (septum, echogenicity, size, or papillary projection) with the cancer risk factor profile.CONCLUSIONS: Although a very small proportion of the clinically silent ovarian abnormalities found on ultrasound are found to be ovarian cancers, the remaining complex cysts and other clinically suspicious abnormalities do not appear to be the immediate precursors of ovarian cancer.

Lung cancer mortality in the Mayo Lung Project: impact of extended follow-up.

BACKGROUND: The Mayo Lung Project (MLP) was a randomized, controlled clinical trial of lung cancer screening that was conducted in 9211 male smokers between 1971 and 1983. The intervention arm was offered chest x-ray and sputum cytology every 4 months for 6 years; the usual-care arm was advised at trial entry to receive the same tests annually. No lung cancer mortality benefit was evident at the end of the study. We have extended follow-up through 1996. METHODS: A National Death Index-PLUS search was used to assign vital status and date and cause of death for 6523 participants with unknown information. The median survival for lung cancer patients diagnosed before July 1, 1983, was calculated by use of Kaplan-Meier estimates. Survival curves were compared with the log-rank test. RESULTS: The median follow-up time was 20.5 years. Lung cancer mortality was 4.4 (95% confidence interval [CI] = 3.9-4.9) deaths per 1000 person-years in the intervention arm and 3.9 (95% CI = 3.5-4.4) in the usual-care arm (two-sided P: for difference =.09). For participants diagnosed with lung cancer before July 1, 1983, survival was better in the intervention arm (two-sided P: =.0039). The median survival for patients with resected early-stage disease was 16.0 years in the intervention arm versus 5.0 years in the usual-care arm. CONCLUSIONS: Extended follow-up of MLP participants did not reveal a lung cancer mortality reduction for the intervention arm. Similar mortality but better survival for individuals in the intervention arm indicates that some lesions with limited clinical relevance may have been identified in the intervention arm.

Investigation of design and bias issues in case-control studies of cancer screening using microsimulation.

Using a microsimulation approach, the authors examined design and bias issues in case-control studies of cancer screening. Specifically, they looked at the impact on the odds ratio of the way in which exposure to screening is defined, the type of age matching, the time scale used, and the criteria used to determine control eligibility. The results showed that defining exposure as "ever/never" screened produced, as expected, a serious bias in favor of screening. Defining exposure as being screened no later than the time the case's cancer is diagnosed has a serious bias against screening. An alternative exposure definition--screening can occur no later than the time the case would have been clinically diagnosed--eliminates the bias against screening. Further, the results showed that the type of age matching and the time scale used can produce a bias against screening and that this bias can be quite strong when case-control studies are performed in populations with a periodic screening program that is the only source of screening. Finally, control eligibility criteria had little effect.

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial of the National Cancer Institute: history, organization, and status.

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is enrolling 148,000 men and women ages 55-74 at ten screening centers nationwide with balanced randomization to intervention and control arms. For prostate cancer, men receive a digital rectal examination and a blood test for prostate-specific antigen. For lung cancer, men and women receive a posteroanterior view chest X-ray. For colorectal cancer, men and women undergo a 60-cm flexible sigmoidoscopy. For ovarian cancer, women receive a blood test for the CA125 tumor marker and transvaginal ultrasound. Members of the control arm continue with their usual care. Follow-up in both groups will continue for at least 13 years from randomization to assess health status and cause of death. The primary endpoint is mortality from the four PLCO cancers, which accounts for about 53% of all cancer deaths in men and 41% of cancer deaths in women in the United States each year. Blood specimens are collected from screened participants, buccal cell DNA from controls, and histology slides from cases; these are maintained in a biorepository. Participants complete a baseline questionnaire (covering health status and risk factors) and a dietary questionnaire. More than 12,000 participants were enrolled in the pilot phase (concluded in September 1994). Changes in the eligibility criteria followed. As of April 2000, enrollment exceeded 144,500. Data are scanned into designated on-site computers for uploading by participant identification number to the coordinating center for quality checks, archival storage, and preparation of analysis datasets for use by the National Cancer Institute (NCI). Scientific direction is provided by NCI scientists, trial investigators, external consultants, and an independent data safety and monitoring board. Performance and data quality are monitored via data edits, site visits, random record audits, and teleconferences. The PLCO trial is formally endorsed by the American Cancer Society and has been ranked by the American Urological Association as one of the most important prostate cancer studies being conducted. Special efforts to enroll black participants are cosponsored by the U.S. Centers for Disease Control and Prevention.

Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

The objectives of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial are to determine in screenees ages 55-74 at entry whether screening with flexible sigmoidoscopy (60-cm sigmoidoscope) can reduce mortality from colorectal cancer, whether screening with chest X-ray can reduce mortality from lung cancer, whether screening men with digital rectal examination (DRE) plus serum prostate-specific antigen (PSA) can reduce mortality from prostate cancer, and whether screening women with CA125 and transvaginal ultrasound (TVU) can reduce mortality from ovarian cancer. Secondary objectives are to assess screening variables other than mortality for each of the interventions including sensitivity, specificity, and positive predictive value; to assess incidence, stage, and survival of cancer cases; and to investigate biologic and/or prognostic characterizations of tumor tissue and biochemical products as intermediate endpoints. The design is a multicenter, two-armed, randomized trial with 37,000 females and 37,000 males in each of the two arms. In the intervention arm, the PSA and CA125 tests are performed at entry, then annually for 5 years. The DRE, TVU, and chest X-ray exams are performed at entry and then annually for 3 years. Sigmoidoscopy is performed at entry and then at the 5-year point. Participants in the control arm follow their usual medical care practices. Participants will be followed for at least 13 years from randomization to ascertain all cancers of the prostate, lung, colorectum, and ovary, as well as deaths from all causes. A pilot phase was undertaken to assess the randomization, screening, and data collection procedures of the trial and to estimate design parameters such as compliance and contamination levels. This paper describes eligibility, consent, and other design features of the trial, randomization and screening procedures, and an outline of the follow-up procedures. Sample-size calculations are reported, and a data analysis plan is presented.

Coordination and management of a large multicenter screening trial: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a large and complex multi-institutional, multifaceted organization with a 20-year horizon. The implementation of the trial began with the creation of an organizational structure that supports strong leadership, cooperation, and effective communication among the trial collaborators including an operational framework for the development, review, and pretest of instruments, data collection, and management procedures; the setting of high-quality standards for training of trial staff; and the development of a comprehensive assessment plan for evaluation of all trial activities. This paper describes the process and methods used in the coordination and management of the PLCO trial. These include the role of the steering committee and its subcommittees and working groups, the establishment of regular and ad hoc communications among collaborators, the training of screening center coordinators and examiners, the PLCO manual of operations and procedures, and the development and implementation of a comprehensive quality assurance plan.

Cancer surveillance series: interpreting trends in prostate cancer--part I: Evidence of the effects of screening in recent prostate cancer incidence, mortality, and survival rates.

BACKGROUND: The prostate-specific antigen test was approved by the U.S. Food and Drug Administration in 1986 to monitor the disease status in patients with prostate cancer and, in 1994, to aid in prostate cancer detection. However, after 1986, the test was performed on many men who had not been previously diagnosed with prostate cancer, apparently resulting in the diagnosis of a substantial number of early tumors. Our purpose is to provide insight into the effect of screening on prostate cancer rates. Detailed data are presented for whites because the size of the population allows for calculating statistically reliable rates; however, similar overall trends are seen for African-Americans and other races. METHODS: Prostate cancer incidence data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program and mortality data from the National Center for Health Statistics were analyzed. RESULTS/CONCLUSIONS: The following findings are consistent with a screening effect: 1) the recent decrease since 1991 in the incidence of distant stage disease, after not having been perturbed by screening; 2) the decline in the incidence of earlier stage disease beginning the following year (i.e., 1992); 3) the recent increases and decreases in prostate cancer incidence and mortality by age that appear to indicate a calendar period effect; and 4) trends in the incidence of distant stage disease by tumor grade and trends in the survival of patients with distant stage disease by calendar year that provide suggestive evidence of the tendency of screening to detect slower growing tumors. IMPLICATIONS: The decline in the incidence of distant stage disease holds the promise that testing for prostate-specific antigen may lead to a sustained decline in prostate cancer mortality. However, population data are complex, and it is difficult to confidently attribute relatively small changes in mortality to any one cause.

Reanalysis of the Mayo Lung Project data: the impact of confounding and effect modification.

OBJECTIVES: To examine whether age at entry, history of cigarette smoking, exposure to non-tobacco lung carcinogens, or previous pulmonary illnesses were confounders or effect modifiers of the relation between screening and lung cancer mortality in the Mayo Lung Project. SETTING: The Mayo Lung Project was a randomised, controlled, clinical trial conducted between 1971 and 1986 in 9211 male smokers over the age of 45 in Minnesota (USA). The group screened received chest x ray examination and sputum cytology every four months for six years. The unscreened group were recommended to obtain usual care (annual chest x ray examination and sputum cytology). After follow up, lung cancer mortality was similar in both groups. METHODS: Proportional hazard models were used to analyse data. A variable was considered a confounder if its inclusion in a model changed the rate ratio for screening by more than 15%; a variable was considered an effect modifier if its stratum-specific rate ratio for screening differed by a factor of two. RESULTS: None of the four aforementioned variables changed the rate ratio associated with screening (1.07) by more than 2%. The effect of screening may have differed by years smoked (rate ratio for smoking fewer than 30 years 2.4; rate ratio for smoking 30 or more years 1.0), though we suspect that this result occurred by chance. CONCLUSION: Adjustment for or stratification by four established lung cancer risk factors did not alter the original findings of the Mayo Lung Project.

Estimation of post-lead-time survival under dependence between lead-time and post-lead-time survival.

Early detection of cancer by screening advances the date of diagnosis, but may or may not alter time to death. Screening programme need to assess the true benefit of screening, that is, the length of time by which survival has been extended, beyond merely the time by which the diagnosis is advanced (lead-time). One method is to estimate the distribution of the time survived post-lead-time using total survival time data for screen-detected cancer cases, under the assumption of independence of the lead-time and the past-lead-time survival. However, it seems biologically reasonable that the lead-time and the post-lead-time survival are positively correlated. This paper investigates the consequences of departures from independence of lead-time and post-lead-time survival on estimation of post-lead-time survival. We introduce a new model that involves dependence between the lead-time and the post-lead-time survival. We show that the new model can be converted to the model discussed by Xu and Prorok. We consider the non-parametric maximum likelihood estimator of the post-lead-time survival under the new model. We apply the method to data from the HIP (Health Insurance Plan of Greater New York) breast cancer screening trial. We make comparisons with the survival of cancer cases not detected by screening, such as interval cases, cases among individuals who refused screening, and randomized control cases.

Estimating a distribution function of the tumor size at metastasis.

In studying the relationship between the size of primary cancers and the occurrence of metastases, two quantities are of prime importance. The first is the distribution of tumor size at the point of metastatic transition, while the second is the probability that detectable metastases are present when cancer comes to medical attention. Kimmel and Flehinger (1991, Biometrics 47, 987-1004) developed a general nonparametric model and studied its two limiting cases. Because of unidentifiablity of their general model, a new identifiable model is introduced by making the hazard function for detecting a metastatic cancer a constant. The new model includes Kimmel and Flehinger's (1991) second limiting model as a special case. An estimator of the tumor size distribution at metastases is proposed. The result is applied to a set of colorectal cancer data.

Case-control studies of cancer screening: theory and practice.

This review summarizes methodologic theories for the design of cancer screening case-control studies and examines the methods applied in studies published in English from 1980 through 1996. In addition to summarizing state-of-the-art methodologic approaches, we identify areas where obvious gaps exist between theory and practice, and we recommend potential areas where theory and methodology may need further development. In particular, we focus on three major areas: 1) the selection of case and control subjects, 2) the definition of exposure (i.e., exposure to the screening test), and 3) bias. Each area is considered carefully by summarizing current theory, reviewing cancer screening applications, and linking recommended methodologic approaches to those used in practice to identify areas where inconsistencies exist. In general, we found methodologic theory and practice in this field of research to be consistent. However, discrepancies were identified in the area of exposure definition, including the use of screening frequency and the use of a detectable, curable preclinical phase for case subjects as the exposure measures. Even when recommended methods were followed, a number of difficulties arose in practice. Specific concerns included the ability to carry out the following: identifying all case subjects within a source population, defining eligibility criteria to ensure that case and control subjects had equal access to screening during the exposure period, distinguishing between symptomatic and diagnostic tests, and controlling for self-selection bias. Careful scrutiny is warranted in all aspects of the design of cancer screening case-control studies, and caution is advised in the interpretation of study results.

Nonparametric estimation of solid cancer size at metastasis and probability of presenting with metastasis at detection.

Two probabilistic characterizations of the relationship between the size of primary cancers and the occurrence of metastases are considered. The first is the distribution of tumor size at the point of metastatic transition, while the second is the probability that detectable metastases are present when cancer comes to medical attention. We show that the general model for this problem developed by Kimmel and Flehinger (1991, Biometrics 47, 987-1004) is unidentifiable. That is, the quantities to be estimated cannot be uniquely determined by the available information. An identifiable model that includes one limiting model of Kimmel and Flehinger (1991) as a special case is developed by using odds ratios. Under the new model, both quantities of interest are estimated by using a nonparametric maximum likelihood approach. The results are applied to two lung cancer data sets.

Prospective evaluation plan for randomised trials of prostate cancer screening. The International Prostate Cancer Screening Trial Evaluation Group.

To enable pooled analyses of continuing and planned randomised trials of prostate cancer screening, guidelines for minimal data required for such analyses were developed in the recent meeting of the International Prostate Screening Trial Evaluation Group (IPSTEG). The aim of the pooled analysis with data on individual level will be: (a) Estimation of the effect of screening on prostate cancer mortality with greater precision than individual studies (b) Assessment of optimal screening procedures and interval (c) Identification of subgroups within the populations that might receive most benefit from screening (d) Evaluation of the quality of life effects and cost effectiveness of screening. All studies included in the combined analysis share a common core protocol with minimum data requirements. The protocol allows, however, adaptation of the procedures to local circumstances within defined options. It should be noted that the process is continuing and the protocol is subject to evaluation and revision in the meetings of the IPSTEG on a regular basis.

Non-parametric estimation of the post-lead-time survival distribution of screen-detected cancer cases.

The goal of screening programmes for cancer is early detection and treatment with a consequent reduction in mortality from the disease. Screening programmes need to assess the true benefit of screening, that is, the length of time of extension of survival beyond the time of advancement of diagnosis (lead-time). This paper presents a non-parametric method to estimate the survival function of the post-lead-time survival (or extra survival time) of screen-detected cancer cases based on the observed total life time, namely, the sum of the lead-time and the extra survival time. We apply the method to the well-known data set of the HIP (Health Insurance Plan of Greater New York) breast cancer screening study. We make comparisons with the survival of other groups of cancer cases not detected by screening such as interval cases, cases among individuals who refused screening, and randomized control cases. As compared with Walter and Stitt's model, in which they made parametric assumptions for the extra survival time, our non-parametric method provides a better fit to HIP data in the sense that our estimator for the total survival time has a smaller sum of squares of residuals.

NIH Consensus 1994: screening.

Frequently, the medical and lay community has assumed that earlier diagnosis of cancer of any type automatically confers benefit and that any diagnostic test that can identify early stages of disease must therefore be useful for screening. However, there is an emerging science of screening which affords a more rigorous approach to public health recommendations in the application of new technologies to screening and early detection. A number of public health groups and agencies are using an evidence-based approach in making recommendations. Using this approach, early detection methods for ovarian cancer would meet only the weakest level of evidence to support their routine application in asymptomatic women. For this reason, the National Cancer Institute has recently launched a large randomized clinical trial to test the effectiveness of screening for ovarian cancer.