Factors Associated With Small Aggressive Non-Small Cell Lung Cancers in the National Lung Screening Trial: A Validation Study.

BACKGROUND: A small proportion of non-small cell lung cancers (NSCLCs) have been observed to spread to distant lymph nodes (N3) or metastasize (M1) or both, while the primary tumor is small (≤3 cm, T1). These small aggressive NSCLCs (SA-NSLSC) are important as they are clinically significant, may identify unique biologic pathways, and warrant aggressive follow-up and treatment. This study identifies factors associated with SA-NSCLC and attempts to validate a previous finding that women with a family history of lung cancer are at particularly elevated risk of SA-NSCLC. METHODS: This study used a case-case design within the National Cancer Institute's National Lung Screening Trial (NLST) cohort. Case patients and "control" patients were selected based on TNM staging parameters. Case patients (n = 64) had T1 NSCLCs that were N3 or M1 or both, while "control" patients (n = 206) had T2 or T3, N0 to N2, and M0 NSCLCs. Univariate and multivariable logistic regression were used to identify factors associated with SA-NSCLC. RESULTS: In bootstrap bias-corrected multivariable logistic regression models, small aggressive adenocarcinomas were associated with a positive history of emphysema (odds ratio [OR] = 5.15, 95% confidence interval [CI] = 1.63 to 23.00) and the interaction of female sex and a positive family history of lung cancer (OR = 6.55, 95% CI = 1.06 to 50.80). CONCLUSIONS: Emphysema may play a role in early lung cancer progression. Females with a family history of lung cancer are at increased risk of having small aggressive lung adenocarcinomas. These results validate previous findings and encourage research on the role of female hormones interacting with family history and genetic factors in lung carcinogenesis and progression.

Sexually transmitted infections, benign prostatic hyperplasia and lower urinary tract symptom-related outcomes: results from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

OBJECTIVE: To examine whether a history of sexually transmitted infections (STIs) or positive STI serology is associated with prevalent and incident benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS)-related outcomes in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. METHODS: Self-reported history of STIs (gonorrhoea, syphilis) was ascertained at baseline, and serological evidence of STIs (Chlamydia trachomatis, Trichomonas vaginalis, human papillomavirus (HPV)-16, HPV-18, herpes simplex virus type 2, human herpesvirus type 8 and cytomegalovirus) was detected in baseline serum specimens. We used data collected on the baseline questionnaire, as well as results from the baseline prostate-specific antigen (PSA) test and digital rectal examination (DRE), to define prevalent BPH/LUTS-related outcomes as evidence of LUTS (self-reported diagnosis of an enlarged prostate/BPH, BPH surgery or nocturia [waking ≥2 times/night to urinate]) and evidence of prostate enlargement (PSA > 1.4 ng/mL or prostate volume ≥30 mL) in men without prostate cancer. We created a similar definition of incident BPH using data from the follow-up questionnaire completed 5-13 years after enrolment (self-reported diagnosis of an enlarged prostate/BPH or nocturia), data on finasteride use during follow-up, and results from the follow-up PSA tests and DREs. We used Poisson regression with robust variance estimation to calculate prevalence ratios (PRs) in our cross-sectional analysis of self-reported (n = 32 900) and serologically detected STIs (n = 1 143) with prevalent BPH/LUTS, and risk ratios in our prospective analysis of self-reported STIs with incident BPH/LUTS (n = 5 226). RESULTS: Generally null results were observed for associations of a self-reported history of STIs and positive STI serologies with prevalent and incident BPH/LUTS-related outcomes, with the possible exception of T. vaginalis infection. This STI was positively associated with prevalent nocturia (PR 1.36, 95% confidence interval (CI) 1.18-1.65), prevalent large prostate volume (PR 1.21 95% CI 1.02-1.43), and any prevalent BPH/LUTS (PR 1.32 95% CI 1.09-1.61); too few men had information on both STI serologies and incident BPH/LUTS to investigate the associations between T. vaginalis infection and incident BPH/LUTS-related outcomes. CONCLUSIONS: Our findings do not support associations of several known STIs with BPH/LUTS-related outcomes, although T. vaginalis infection may warrant further study.

PLCO: Evolution of an Epidemiologic Resource and Opportunities for Future Studies.

The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), a large-scale, multi-institutional, randomized controlled trial, was launched in 1992 to evaluate the effectiveness of screening modalities for prostate, lung, colorectal, and ovarian cancer. However, PLCO was additionally designed to serve as an epidemiologic resource and the National Cancer Institute has invested substantial resources over the years to accomplish this goal. In this report, we provide a summary of changes to PLCO's follow-up after conclusion of the screening phase of the trial and highlight recent data and biospecimen collections, including ancillary studies, geocoding, administration of a new medication use questionnaire, consent for linkage to Medicare, and additional tissue collection that enhance the richness of the PLCO resource and provide further opportunities for scientific investigation into the prevention, early detection, etiology and treatment of cancer.

Lessons in Medical Record Abstraction from the Prostate, Lung, Colorectal, and Ovarian (PLCO) National Screening Trial.

The most rigorous and accurate approach to evaluating clinical events in cancer screening studies is to use data obtained through medical record abstraction (MRA). Although MRA is complex, the particulars of the procedure-such as the specific training and quality assurance processes, challenges of implementation, and other factors that influence the quality of abstraction--are usually not described in reports of studies that employed the technique. In this paper, we present the details of MRA activities used in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, which used MRA to determine primary and secondary outcomes and collect data on other clinical events. We describe triggers of the MRA cycle and the specific tasks that were part of the abstraction process. We also discuss training and certification of abstracting staff, and technical methods and communication procedures used for data quality assurance. We include discussion of challenges faced and lessons learned.

Physical activity and benign prostatic hyperplasia-related outcomes and nocturia.

INTRODUCTION: Benign prostatic hyperplasia (BPH) and its associated lower urinary tract symptoms (LUTS), including nocturia, are extremely common among middle- and older-age American men. Although studies on physical activity (PA) and prevalent BPH-related outcomes suggest that PA may protect against the development of this common condition, only a few studies have examined the relation between PA and incident BPH-related outcomes and LUTS with mixed findings. In addition, although nocturia is the most commonly reported and most bothersome LUTS in men with or without evidence of BPH, few studies have examined the association of PA and nocturia independent of BPH. The purpose of this analysis was to examine the association of PA with BPH-related outcomes and nocturia in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial. METHODS: We examined this association with both prevalent (n = 28,404) and incident (n = 4710) BPH-related outcomes (measured by self-report of physician diagnosis, BPH surgery, finasteride use, and clinical indicators) and nocturia. Poisson regression with robust variance was used to calculate prevalence ratios and relative risks. RESULTS: PA was weakly positively associated with several prevalent BPH-related outcomes and was strongly inversely associated with prevalent nocturia. In incident analyses, PA was only associated with nocturia. Men who were active ≥1 h·wk(-1) were 13% less likely (95% confidence interval, 2%-22%) to report nocturia and 34% less likely (95% confidence interval, 15%-49%) to report severe nocturia as compared with men who reported no PA. The associations were similar for men with and without additional BPH-related outcomes, except for prevalent nocturia, where the association was stronger for men without other BPH-related outcomes. CONCLUSIONS: Combined with other management strategies, PA may provide a strategy for the management of BPH-related outcomes, particularly nocturia.

Interval lung cancers not detected on screening chest X-rays: How are they different?

BACKGROUND: The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial provides us an opportunity to describe interval lung cancers not detected by screening chest X-ray (CXR) compared to screen-detected cancers. METHODS: Participants were screened for lung cancer with CXR at baseline and annually for two (never smokers) or three (ever smokers) more years. Screen-detected cancers were those with a positive CXR and diagnosed within 12 months. Putative interval cancers were those with a negative CXR screen but with a diagnosis of lung cancer within 12 months. Potential interval cancers were re-reviewed to determine whether lung cancer was missed and probably present during the initial interpretation or whether the lesion was a "true interval" cancer. RESULTS: 77,445 participants were randomized to the intervention arm with 70,633 screened. Of 5227 positive screens from any screening round, 299 resulted in screen-detected lung cancers; 151 had potential interval cancers with 127 CXR available for re-review. Cancer was probably present in 45/127 (35.4%) at time of screening; 82 (64.6%) were "true interval" cancers. Compared to screen-detected cancers, true interval cancers were more common among males, persons with <12 years education and those with a history of smoking. True interval lung cancers were more often small cell, 28.1% vs. 7.4%, and less often adenocarcinoma, 25.6% vs. 56.2% (p<0.001), more advanced stage IV (30.5% vs. 16.6%, p<0.02), and less likely to be in the right upper lobe, 17.1% vs. 36.1% (p<0.02). CONCLUSION: True interval lung cancers differ from CXR-screen-detected cancers with regard to demographic variables, stage, cell type and location. ClinicalTrials.gov number: NCT00002540.

Diagnostic evaluation following a positive lung screening chest radiograph in the Prostate, Lung, Colorectal, Ovarian (PLCO) Cancer Screening Trial.

Lung cancer is the major cause of cancer mortality. One of the aims of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) was to determine if annual screening chest radiographs reduce lung cancer mortality. We enrolled 154,900 individuals, aged 55-74 years; 77,445 were randomized to the intervention arm and received an annual chest radiograph for 3 or 4 years. Participants with a positive screen underwent diagnostic evaluation under guidance of their primary physician. Methods of diagnosis or exclusion of cancer, interval from screen to diagnosis, and factors predicting diagnostic testing were evaluated. One or more positive screens occurred in 17% of participants. Positive screens resulted in biopsy in 3%, with 54% positive for cancer. Biopsy likelihood was associated with a mass, smoking, age, and family history of lung cancer. Diagnostic testing stopped after a chest radiograph or computed tomography/magnetic resonance imaging in over half. After a second or subsequent positive screen, evaluation stopped after comparison to prior radiographs in over half. Of 308 screen-detected cancers, the diagnosis was established by thoracotomy/thoracoscopy in 47.7%, needle biopsy in 27.6%, bronchoscopy in 20.1% and mediastinoscopy in 2.9%. Eighty-four percent of screen-detected lung cancers were diagnosed within 6 months. Diagnostic evaluations following a positive screen were conducted in a timely fashion. Lung cancer was diagnosed by tissue biopsy or cytology in all cases. Lung cancer was excluded during evaluation of positive screening examinations by clinical or radiographic evaluation in all but 1.4% who required a tissue biopsy.

Assessing the risk of ovarian malignancy in asymptomatic women with abnormal CA 125 and transvaginal ultrasound scans in the prostate, lung, colorectal, and ovarian screening trial.

OBJECTIVE: To estimate the risk of ovarian malignancy among asymptomatic women with abnormal transvaginal ultrasound scans or CA 125 and to provide guidance to physicians managing these women. METHODS: A cohort of women from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial with abnormal ovarian results at the initial (T0) and subsequent (T1+) screens were analyzed to estimate which findings were associated with high risk of ovarian cancer. Cancer risks more than 10% were designated as high and risks of 3% or less were designated as low. RESULTS: For the T0 screen, two high-risk categories were identified: CA 125 of 70 or more with negative transvaginal ultrasound scan (positive predictive value [PPV] 15.9%, CI 14.7-17.7%); and positive for both CA 125 and transvaginal ultrasound scan (PPV 25.0%, CI 23.3-27.3%). For T1+ screens, three high-risk categories were identified: negative transvaginal ultrasound scan with change in CA 125 of 45 or more (PPV 29.0%, CI 28.3-30.3%); increase in size of cyst 6 cm or more with negative CA 125 (PPV 13.3%, CI 10.5-18.0%); and positive for both tests (PPV 42.9%, CI 40.0-46.0%). High-risk criteria for T0 provide a sensitivity of 60%, specificity of 96.2%, PPV of 19.7%, and a negative predictive value (NPV) of 99.3%. T1+ criteria yielded a sensitivity of 85.3%, specificity of 95.6%, PPV of 29.6%, and NPV of 99.7%. CONCLUSIONS: High-risk categories for predicting risk of cancer in women with abnormal CA 125, transvaginal ultrasound scan, or both at initial and subsequent screens have been identified. The large number of women in this study, the 4-year complete follow-up, and small number of invasive cancers in the low-risk categories provide guidance for clinical decisions regarding need for surgery in these women. LEVEL OF EVIDENCE: II.

Non-steroidal anti-inflammatory drug use and the risk of benign prostatic hyperplasia-related outcomes and nocturia in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

UNLABELLED: Study Type - Therapy (cohort) Level of Evidence 4. What's known on the subject? and What does the study add? Accumulating evidence suggests that inflammation may contribute to the development of BPH and LUTS. Therefore, it is plausible that anti-inflammatory agents, such as aspirin and other NSAIDs, may reduce the risk of BPH/LUTS, as was observed in a recent analysis of daily aspirin use and BPH/LUTS risk in the Olmsted County Study of Urinary Symptoms and Health Status in Men. The present study, conducted in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, found no association for recent aspirin or ibuprofen use with the risk of BPH/LUTS. OBJECTIVE: To investigate the relationship between non-steroidal anti-inflammatory drug (NSAID) use and the incidence of benign prostatic hyperplasia (BPH)-related outcomes and nocturia, a lower urinary tract symptom (LUTS) of BPH, in light of accumulating evidence suggesting a role for inflammation in BPH/LUTS development. PATIENTS AND METHODS: At baseline, participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial completed questions on recent, regular aspirin and ibuprofen use, BPH surgery, diagnosis of an enlarged prostate/BPH, and nocturia. Participants in the intervention arm also underwent a digital rectal examination (DRE), from which prostate dimensions were estimated, as well as a prostate-specific antigen (PSA) test. Only participants in the intervention arm without BPH/LUTS at baseline were included in the analysis (n= 4771). • During follow-up, participants underwent annual DREs and PSA tests, provided annual information on finasteride use, and completed a supplemental questionnaire in 2006-2008 that included additional questions on diagnosis of an enlarged prostate/BPH and nocturia. • Information collected was used to investigate regular aspirin or ibuprofen use in relation to the incidence of six BPH/LUTS definitions: diagnosis of an enlarged prostate/BPH, nocturia (waking two or more times per night to urinate), finasteride use, any self-reported BPH/LUTS, prostate enlargement (estimated prostate volume ≥30 mL on any follow-up DRE) and elevation in PSA level (>1.4 ng/mL on any follow-up PSA test). RESULTS: Generally, null results were observed for any recent, regular aspirin or ibuprofen use (risk ratio = 0.92-1.21, P= 0.043-0.91) and frequency of use (risk ratios for one category increase in NSAID use = 0.98-1.11, P-trends = 0.10-0.99) with incident BPH/LUTS. CONCLUSION: The findings obtained in the present study do not support a protective role for recent NSAID use in BPH/LUTS development.

Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up.

BACKGROUND: The prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was undertaken to determine whether there is a reduction in prostate cancer mortality from screening using serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE). Mortality after 7-10 years of follow-up has been reported previously. We report extended follow-up to 13 years after the trial. METHODS: A total of 76 685 men, aged 55-74 years, were enrolled at 10 screening centers between November 1993 and July 2001 and randomly assigned to the intervention (organized screening of annual PSA testing for 6 years and annual DRE for 4 years; 38 340 men) and control (usual care, which sometimes included opportunistic screening; 38 345 men) arms. Screening was completed in October 2006. All incident prostate cancers and deaths from prostate cancer through 13 years of follow-up or through December 31, 2009, were ascertained. Relative risks (RRs) were estimated as the ratio of observed rates in the intervention and control arms, and 95% confidence intervals (CIs) were calculated assuming a Poisson distribution for the number of events. Poisson regression modeling was used to examine the interactions with respect to prostate cancer mortality between trial arm and age, comorbidity status, and pretrial PSA testing. All statistical tests were two-sided. RESULTS: Approximately 92% of the study participants were followed to 10 years and 57% to 13 years. At 13 years, 4250 participants had been diagnosed with prostate cancer in the intervention arm compared with 3815 in the control arm. Cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10 000 person-years, respectively, resulting in a relative increase of 12% in the intervention arm (RR = 1.12, 95% CI = 1.07 to 1.17). After 13 years of follow-up, the cumulative mortality rates from prostate cancer in the intervention and control arms were 3.7 and 3.4 deaths per 10 000 person-years, respectively, resulting in a non-statistically significant difference between the two arms (RR = 1.09, 95% CI = 0.87 to 1.36). No statistically significant interactions with respect to prostate cancer mortality were observed between trial arm and age (P(interaction) = .81), pretrial PSA testing (P(interaction) = .52), and comorbidity (P(interaction) = .68). CONCLUSIONS: After 13 years of follow-up, there was no evidence of a mortality benefit for organized annual screening in the PLCO trial compared with opportunistic screening, which forms part of usual care, and there was no apparent interaction with age, baseline comorbidity, or pretrial PSA testing.

Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial.

CONTEXT: The effect on mortality of screening for lung cancer with modern chest radiographs is unknown. OBJECTIVE: To evaluate the effect on mortality of screening for lung cancer using radiographs in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial that involved 154,901 participants aged 55 through 74 years, 77,445 of whom were assigned to annual screenings and 77,456 to usual care at 1 of 10 screening centers across the United States between November 1993 and July 2001. The data from a subset of eligible participants for the National Lung Screening Trial (NLST), which compared chest radiograph with spiral computed tomographic (CT) screening, were analyzed. INTERVENTION: Participants in the intervention group were offered annual posteroanterior view chest radiograph for 4 years. Diagnostic follow-up of positive screening results was determined by participants and their health care practitioners. Participants in the usual care group were offered no interventions and received their usual medical care. All diagnosed cancers, deaths, and causes of death were ascertained through the earlier of 13 years of follow-up or until December 31, 2009. MAIN OUTCOME MEASURES: Mortality from lung cancer. Secondary outcomes included lung cancer incidence, complications associated with diagnostic procedures, and all-cause mortality. RESULTS: Screening adherence was 86.6% at baseline and 79% to 84% at years 1 through 3; the rate of screening use in the usual care group was 11%. Cumulative lung cancer incidence rates through 13 years of follow-up were 20.1 per 10,000 person-years in the intervention group and 19.2 per 10,000 person-years in the usual care group (rate ratio [RR]; 1.05, 95% CI, 0.98-1.12). A total of 1213 lung cancer deaths were observed in the intervention group compared with 1230 in usual care group through 13 years (mortality RR, 0.99; 95% CI, 0.87-1.22). Stage and histology were similar between the 2 groups. The RR of mortality for the subset of participants eligible for the NLST, over the same 6-year follow-up period, was 0.94 (95% CI, 0.81-1.10). CONCLUSION: Annual screening with chest radiograph did not reduce lung cancer mortality compared with usual care. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00002540.

Genetic variation on 9p22 is associated with abnormal ovarian ultrasound results in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

BACKGROUND: A recent ovarian cancer genome-wide association study (GWAS) identified a locus on 9p22 associated with reduced ovarian cancer risk. The single nucleotide polymorphism (SNP) markers localize to the BNC2 gene, which has been associated with ovarian development. METHODS: We analyzed the association of 9p22 SNPs with transvaginal ultrasound (TVU) screening results and CA-125 blood levels from participants without ovarian cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO); 1,106 women with adequate ultrasound screening results and available genotyping information were included in the study. RESULTS: We observed a significantly increased risk of abnormal suspicious TVU results for seven SNPs on 9p22, with odds ratios between 1.68 (95% CI: 1.04-2.72) for rs4961501 and 2.10 (95% CI: 1.31-3.38) for rs12379183. Associations were restricted to abnormal suspicious findings at the first TVU screen. We did not observe an association between 9p22 SNPs and CA-125 levels. CONCLUSIONS: Our findings suggest that 9p22 SNPs, which were found to be associated with decreased risk of ovarian cancer in a recent GWAS, are associated with sonographically detectable ovarian abnormalities. Our results corroborate the relevance of the 9p22 locus for ovarian biology. Further studies are required to understand the complex relationship between screening abnormalities and ovarian carcinogenesis and to evaluate whether this locus can influence the risk stratification of ovarian cancer screening.

Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial.

CONTEXT: Screening for ovarian cancer with cancer antigen 125 (CA-125) and transvaginal ultrasound has an unknown effect on mortality. OBJECTIVE: To evaluate the effect of screening for ovarian cancer on mortality in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of 78,216 women aged 55 to 74 years assigned to undergo either annual screening (n = 39,105) or usual care (n = 39,111) at 10 screening centers across the United States between November 1993 and July 2001. Intervention The intervention group was offered annual screening with CA-125 for 6 years and transvaginal ultrasound for 4 years. Participants and their health care practitioners received the screening test results and managed evaluation of abnormal results. The usual care group was not offered annual screening with CA-125 for 6 years or transvaginal ultrasound but received their usual medical care. Participants were followed up for a maximum of 13 years (median [range], 12.4 years [10.9-13.0 years]) for cancer diagnoses and death until February 28, 2010. MAIN OUTCOME MEASURES: Mortality from ovarian cancer, including primary peritoneal and fallopian tube cancers. Secondary outcomes included ovarian cancer incidence and complications associated with screening examinations and diagnostic procedures. RESULTS: Ovarian cancer was diagnosed in 212 women (5.7 per 10,000 person-years) in the intervention group and 176 (4.7 per 10,000 person-years) in the usual care group (rate ratio [RR], 1.21; 95% confidence interval [CI], 0.99-1.48). There were 118 deaths caused by ovarian cancer (3.1 per 10,000 person-years) in the intervention group and 100 deaths (2.6 per 10,000 person-years) in the usual care group (mortality RR, 1.18; 95% CI, 0.82-1.71). Of 3285 women with false-positive results, 1080 underwent surgical follow-up; of whom, 163 women experienced at least 1 serious complication (15%). There were 2924 deaths due to other causes (excluding ovarian, colorectal, and lung cancer) (76.6 per 10,000 person-years) in the intervention group and 2914 deaths (76.2 per 10,000 person-years) in the usual care group (RR, 1.01; 95% CI, 0.96-1.06). CONCLUSIONS: Among women in the general US population, simultaneous screening with CA-125 and transvaginal ultrasound compared with usual care did not reduce ovarian cancer mortality. Diagnostic evaluation following a false-positive screening test result was associated with complications. Trial Registration clinicaltrials.gov Identifier: NCT00002540.

Pathologic findings following false-positive screening tests for ovarian cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial.

OBJECTIVE: In the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), ovarian cancer screening with transvaginal ultrasound (TVU) and CA-125 produced a large number of false-positive tests. We examined relationships between histopathologic diagnoses, false-positive test group, and participant and screening test characteristics. METHODS: The PLCO ovarian cancer screening arm included 39,105 women aged 55-74 years assigned to annual CA-125 and TVU. Histopathologic diagnoses from women with false-positive tests and subsequent surgery were reviewed in this analysis: all CA125+ (n=121); all CA125+/TVU+ (n=46); and a random sample of TVU+ (n=373). Demographic and ovarian cancer risk factor data were self-reported. Pathologic diagnoses were abstracted from surgical pathology reports. We compared participant characteristics and pathologic diagnoses by category of false-positive using Pearson χ2, Fisher's exact, or Wilcoxon-Mann-Whitney tests. RESULTS: Women with a false-positive TVU were younger (P<0.001), heavier (P<0.001), and reported a higher frequency of prior hysterectomy (P<0.001). Serous cystadenoma, the most common benign ovarian diagnosis, was more frequent among women with TVU+ compared to CA-125+ and CA-125+/TVU+ (P<0.001). Benign non-ovarian findings were commonly associated with all false-positives, although more frequently with CA-125+ than TVU+ or CA-125+/TVU+ groups (P=0.019). Non-ovarian cancers were diagnosed most frequently among CA-125+ (P<0.001). CONCLUSIONS: False-positive ovarian cancer screening tests were associated with a range of histopathologic diagnoses, some of which may be related to patient and screening test characteristics. Further research into the predictors of false-positive ovarian cancer screening tests may aid efforts to reduce false-positive results.

Lung cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.

BACKGROUND: The 5-year overall survival rate of lung cancer patients is approximately 15%. Most patients are diagnosed with advanced-stage disease and have shorter survival rates than patients with early-stage disease. Although screening for lung cancer has the potential to increase early diagnosis, it has not been shown to reduce lung cancer mortality rates. In 1993, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was initiated specifically to determine whether screening would reduce mortality rates from PLCO cancers. METHODS: A total of 77 464 participants, aged 55-74 years, were randomly assigned to the intervention arm of the PLCO Cancer Screening Trial between November 8, 1993, and July 2, 2001. Participants received a baseline chest radiograph (CXR), followed by three annual single-view CXRs at the 10 US screening centers. Cancers were classified as screen detected and nonscreen detected (interval or never screened) and according to tumor histology. The positivity rates of screen-detected cancers and positive predictive values (PPVs) were calculated. Because 51.6% of the participants were current or former smokers, logistic regression analysis was performed to control for smoking status. All statistical tests were two-sided. RESULTS: Compliance with screening decreased from 86.6% at baseline to 78.9% at the last screening. Overall positivity rates were 8.9% at baseline and 6.6%-7.1% at subsequent screenings; positivity rates increased modestly with smoking risk categories (P(trend) < .001). The PPVs for all participants were 2.0% at baseline and 1.1%, 1.5%, and 2.4% at years 1, 2, and 3, respectively; PPVs in current smokers were 5.9% at baseline and 3.3%, 4.2%, and 5.6% at years 1, 2, and 3, respectively. A total of 564 lung cancers were diagnosed, of which 306 (54%) were screen-detected cancers and 87% were non-small cell lung cancers. Among non-small cell lung cancers, 59.6% of screen-detected cancers and 33.3% of interval cancers were early (I-II) stage. CONCLUSIONS: The PLCO Cancer Screening Trial demonstrated the ability to recruit, retain, and screen a large population over multiple years at multiple centers. A higher proportion of screen-detected lung cancers were early stage, but a conclusion on the effectiveness of CXR screening must await final PLCO results, which are anticipated at the end of 2015.

Prevalence, incidence, and natural history of simple ovarian cysts among women >55 years old in a large cancer screening trial.

OBJECTIVE: The purpose of this study was to measure the occurrence and natural history of simple ovarian cysts in a cohort of older women. STUDY DESIGN: Simple cysts were ascertained among a cohort of 15,735 women from the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial through 4 years of transvaginal ultrasound screening. RESULTS: Simple cysts were seen in 14% of women the first time that their ovaries were visualized. The 1-year incidence of new simple cysts was 8%. Among ovaries with 1 simple cyst at the first screen, 54% retained 1 simple cyst, and 32% had no cyst 1 year later. Simple cysts did not increase risk of subsequent invasive ovarian cancer. CONCLUSION: Simple ovarian cysts are fairly common among postmenopausal women, and most cysts appear stable or resolve by the next annual examination. These findings support recent recommendations to follow unilocular simple cysts in postmenopausal women without intervention.

Prediction of true positive lung cancers in individuals with abnormal suspicious chest radiographs: a prostate, lung, colorectal, and ovarian cancer screening trial study.

INTRODUCTION: Chest radiographs are routinely employed in clinical practice. Radiographic findings that are abnormal suspicious (AS) for lung cancer occur commonly. The majority of AS radiographic abnormalities are not cancer. This study identifies predictors of true positive (TP) AS and presents models for estimating the probability of lung cancer. METHODS: This is a prospective cohort study nested in the randomized National Cancer Institute's Prostate Lung Colorectal Ovarian Cancer Screening Trial (PLCO). First-time AS screens in the screening arm of the PLCO were studied. Associations between nonradiographic and radiographic factors, and TP AS were evaluated by multiple logistic regression. RESULTS: The PLCO intervention arm had 77,465 individuals, of whom 12,314 were AS and of these 232 (1.9%) had lung cancer (were TP). Important independent predictors of TP were older age, lower education, greater pack years and duration smoking history, body mass index <30, family history of lung cancer, lung nodule, lung mass, unilateral mediastinal or hilar lymphadenopathy, lung infiltrate, and upper/middle chest AS location. The model including these variables had a receiver operator characteristic area under the curve (ROC AUC) of 86.4%. This model excluding the smoking variables had an ROC AUC of 77.1% and excluding all nonradiographic variables had an ROC AUC of 73.3% (p < 0.0001 for all these model differences). Smoking and nonsmoking nonradiographic variables significantly added to prediction. CONCLUSION: This study identifies important nonradiographic and radiographic predictors of lung cancer, and presents an accurate model for estimating the probability of lung cancer in individuals with suspicious radiographs. These findings may be of value for screening, research, and patient and clinician decision-making.

Serum prostate-specific antigen hemodilution among obese men undergoing screening in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

BACKGROUND: Previous studies have shown an inverse relationship between prostate-specific antigen (PSA) concentration and body mass index (BMI). It has been recently proposed that this relationship may be explained by the larger plasma volume of obese men diluting a fixed amount of PSA (hemodilution effect). We examined this hypothesis in a cohort of men enrolled in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. METHODS: Of 38,349 men ages 55 to 74 years randomized in PLCO to receive annual PSA and digital rectal examination screening, 28,380 had a baseline PSA, complete demographic information, and no prostate cancer diagnosis within 6 years from baseline. Self-reported height and weight were used to calculate BMI and to estimate plasma volume. PSA mass was estimated as PSA concentration times plasma volume. Multivariable linear regression models were used to investigate the relationship between PSA concentration, plasma volume, PSA mass, and BMI. RESULTS: PSA concentration significantly decreased with increasing BMI (P<0.001); mean PSA values were 1.27, 1.25, 1.18, and 1.07 ng/mL among normal (BMI, 18.5-25), overweight (BMI, 25-30), obese (BMI, 30-35), and morbidly obese (BMI, >35) men, respectively. However, plasma volume also increased with increasing BMI and PSA mass showed no association with BMI, with mean values of 3.78, 3.95, 3.97, and 3.82 microg across the four BMI categories (P=0.10). CONCLUSIONS: This study confirms earlier findings that the inverse relationship between PSA concentration and BMI may be explained by a hemodilution effect. These findings could have implications for prostate cancer screening in large men.

Results from four rounds of ovarian cancer screening in a randomized trial.

OBJECTIVE: To test whether annual screening with transvaginal ultrasonography and CA 125 reduces ovarian cancer mortality. METHODS: Data from the first four annual screens, denoted T0-T3, are reported. A CA 125 value at or above 35 units/mL or an abnormality on transvaginal ultrasonography was considered a positive screen. Diagnostic follow-up of positive screens was performed at the discretion of participants' physicians. Diagnostic procedures and cancers were tracked and verified through medical records. RESULTS: Among 34,261 screening arm women without prior oophorectomy, compliance with screening ranged from 83.1% (T0) to 77.6% (T3). Screen positivity rates declined slightly with transvaginal ultrasonography, from 4.6 at T0 to 2.9-3.4 at T1-T3; CA 125 positivity rates (range 1.4-1.8%) showed no time trend. Eighty-nine invasive ovarian or peritoneal cancers were diagnosed; 60 were screen detected. The positive predictive value (PPV) and cancer yield per 10,000 women screened on the combination of tests were similar across screening rounds (range 1.0-1.3% for PPV and 4.7-6.2 for yield); however, the biopsy (surgery) rate among screen positives decreased from 34% at T0 to 15-20% at T1-T3. The overall ratio of surgeries to screen-detected cancers was 19.5:1. Seventy-two percent of screen-detected cases were late stage (III/IV). CONCLUSION: Through four screening rounds, the ratio of surgeries to screen-detected cancers was high, and most cases were late stage. However, the effect of screening on mortality is as yet unknown. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00002540 LEVEL OF EVIDENCE: II.

Prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian cancer screening trial: update on findings from the initial four rounds of screening in a randomized trial.

OBJECTIVE: To describe the results of the first four rounds (T0-T3) of prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial (designed to determine the value of screening in the four cancers), that for prostate cancer is evaluating whether annual screening with prostate-specific antigen (PSA) and a digital rectal examination (DRE) reduces prostate cancer-specific mortality. SUBJECTS AND METHODS: In all, 38 349 men aged 55-74 years were randomized to undergo annual screening with PSA (abnormal >4.0 ng/mL) and a DRE. The follow-up of abnormal screening results was at the discretion of subjects' physicians. PLCO staff obtained records related to diagnostic follow-up of positive screen results. RESULTS: Compliance with screening decreased slightly from 89% at baseline to 85% at T3. Both PSA positivity rates (range 7.7-8.8% at T0-T3) and DRE positivity rates (range 6.8-7.6% at T0-T3) were relatively constant over time. The positive predictive value (PPV) of a PSA level of >4.0 ng/mL decreased from 17.9% at T0 to 10.4-12.3% at T1-T3; the PPV for DRE (in the absence of a positive PSA test) was constant over time (2.9-3.6%). Cancer was diagnosed in 1902 men (4.9%). Screen-detected cancers at T0 (549) were more likely to be clinical stage III/IV (5.8%) and to have a Gleason score of 7-10 (34%) than screen-detected cancers at T1-T3 (1.5-4.2% stage III/IV and 24-27% Gleason score 7-10 among 1054 cases). CONCLUSION: The present findings on serial prostate screening are similar to those reported from other multi-round screening studies. Determining the effect of PSA screening on prostate cancer mortality awaits further follow-up.