National Cancer Institute

The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial: Questions and Answers

1. What is the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial? 
   The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a large, randomized study to determine whether the use of certain screening tests will reduce the risk of dying of those four cancers. In addition to answering questions about the screening tests, the PLCO asked questions about many aspects of the study participants’ health and collected biospecimens (blood and some tissues) to answer many other questions about cancer.
   
   Ten screening centers located across the United States enrolled nearly 155,000 people ages 55 to 74 with no previous history of prostate, lung, colorectal, or ovarian cancer.  These participants were randomized to either an intervention arm (an organized screening program within the trial) or control arm (which received the usual care from their healthcare providers and which sometimes included screening.)
   
   PLCO centers began enrolling participants in 1993 and completed enrollment in 2001. Trial participants are unpaid volunteers recruited from the general population in the geographic area of each of the screening centers; there were approximately 78,000 women and 76,000 men enrolled in the study. Participants at each screening center fell into four age groups: 55-59 (33% of participants), 60-64 (31%), 65-69 (23%) and 70-74 (13%) at the beginning of the trial.
   
   
2. Why choose these cancers?
   Together, prostate, lung, colorectal, and ovarian cancers account for almost 40 percent of the cancers diagnosed each year and for 44 percent of cancer deaths.  More than 625,000 Americans are expected to be diagnosed with these cancers in 2012 and more than 250,000 will likely die of these diseases.
   
   
3. Where were the PLCO Screening Centers located?
   The 10 PLCO Centers were:
   • Georgetown University Medical Center, Washington, D.C.
   • Henry Ford Health System, Detroit
   • Marshfield Clinical Research Foundation, Marshfield, Wis.
   • Pacific Health Research and Education Institute, Honolulu
   • University of Alabama at Birmingham, Birmingham, Ala
   • University of Colorado, Aurora, Colo.
   • University of Minnesota, Minneapolis
   • University of Pittsburgh, Pittsburgh
   • University of Utah, Salt Lake City, with a satellite in Boise, Idaho
   • Washington University, St. Louis
   
   See the sites on a map at http://prevention.cancer.gov/research-networks/plco.htm.
   
   
4. What cancer screening tests did the participants in the intervention arm receive?
   Participants included in the intervention arm of the trial received appropriate screening for the PLCO cancers during their first six years on the trial. The tests were:
   
   For prostate cancer:
   Digital rectal examination (DRE): An examination in which a doctor inserts a lubricated, gloved finger into the rectum to feel for abnormalities on the prostate gland located near the rectum.
   
   Blood test for prostate-specific antigen (PSA): Measurement of a protein made by the prostate gland and found in the blood. PSA blood levels may be higher than normal in men who have prostate cancer, benign prostatic hyperplasia (BPH), or infection or inflammation of the prostate gland.
   
   For lung cancer:
   Single-view chest X-ray:  An X-ray of the structures inside the chest. X-rays in this trial were a type of radiation delivered at low doses that can go through the body and onto film, making pictures of areas inside the chest, and can be used to diagnose disease.
   
   For colorectal cancer:
   Sigmoidoscopy: Examination of the lower 60 centimeters (about 24 inches) of the colon using a flexible sigmoidoscope, inserted into the rectum. A sigmoidoscope is a thin, tube-like instrument with a light and a lens for viewing.
   
   For ovarian cancer:
   Transvaginal ultrasound (TVU): A procedure used to examine the vagina, uterus, fallopian tubes, ovaries, and bladder. An instrument is inserted into the vagina that causes sound waves to bounce off organs inside the pelvis. These sound waves create echoes that are sent to a computer, which creates a picture called a sonogram.
   
   Blood test for CA-125: Measurement of a substance that may be found in high amounts in the blood of patients with certain types of cancer, including ovarian cancer.
   
   
5. How often did the participants get these tests?
   Men received a digital rectal examination annually for the first 4 years, a PSA blood test annually for 6 years, a chest X-ray annually for 4 years, and a sigmoidoscopy exam upon entry to the trial and a second exam either 3 or 5 years later. 
   
   Women received a chest X-ray annually for 4 years, CA-125 blood test annually for 6 years, transvaginal ultrasound yearly for 4 years, and flexible sigmoidoscopy at the beginning of the trial and either 3 years or 5 years later. 
   
   The participants received follow-up questionnaires via mail for at least 13 years from the time they were randomized.
   
   
6. What tests did the control arm participants receive?
   Participants in the control arm were followed for 13 years after enrollment, but did not receive screening examinations from the PLCO study staff.  They were able to receive these and other cancer screening tests on their own, and PLCO study staff estimated how often that occurred from periodic questionnaires administered to a sample of the control participants.
   
   
7. What are the main findings of the cancer screening part of the PLCO? 
   For colorectal cancer:  PLCO results showed that colorectal cancer screening with flexible sigmoidoscopy decreased both the incidence (21%) and death from the disease (26%) over an average of almost 12 years when compared to the usual care group. In other words, for every 1,000 people who would be tested for colorectal cancer like the people in PLCO and followed for 10 years, there would be about 3 fewer cases of colorectal cancer and 1 less death from the disease.  This is similar to other tests to screen for colorectal cancer. 
   
   For lung cancer:  Participants in the trial who were randomly assigned to receive an annual chest X-ray for 4 consecutive years (only 3 years for never smokers) had nearly the same mortality rate from lung cancer as participants randomly assigned to receive usual care. Only 10 percent of participants were current smokers and 42 percent were former smokers, so many participants were already at low risk of developing lung cancer.  When PLCO researchers looked at the subset of about 30,000 patients in the trial who had a strong smoking history, there was a suggestion of a slight reduction in lung cancer mortality risk associated with screening at 6 and 13 years of follow-up. This finding, however, was not statistically significant and may have been due to chance.  Chest X-rays have not been shown to be effective as a screening test for lung cancer.
   
   For ovarian cancer:  The PLCO results showed that screening with CA-125 and transvaginal ultrasound increased the number of ovarian cancers diagnosed but did not reduce the number of deaths from these cancers. In addition, the necessary tests to evaluate any abnormal screening tests were associated with complications, some of which were quite serious. Of 3,285 women with false-positive results, 1,080 underwent surgical follow-up; of whom, 163 women experienced at least one serious complication (15%).  Combined testing with transvaginal ultrasound and CA-125, as done in PLCO, was not shown to be effective as a screening test for ovarian cancer.
   
   For prostate cancer:  After 13 years of follow up, men who underwent annual prostate cancer screening with PSA testing and DRE had a 12 percent higher incidence of prostate cancer than men in the control group but the same rate of death from the disease. It should be noted that men in the control arm also had PSA screening frequently. No evidence of a mortality benefit was seen overall or in subgroups defined by age, the presence of other illnesses, or pre-trial PSA testing.  However, there were harms associated with follow-ups of abnormal screening tests and with treatments.
   
   
8. What other information was collected from study participants?
   Trial data include screening data, baseline and follow-up health and risk factor data, dietary data, health status, and the collection of blood and other biological samples that are supporting molecular, behavioral and risk studies in early detection and etiology.
   
   All PLCO participants answered questions about sociodemographics, family history, medical history, smoking history, and cancer screening history when they joined the trial. Those in the intervention arm were asked about food consumption, cooking practices, and use of nutritional supplements twice; control arm participants were asked once.  In 2006-2007, all PLCO participants were also asked to provide updated information about their medical history and family history and some additional questions about cancer risk factors such as detailed hormone use and smoking information that was not asked at the beginning of the trial.
   
   Blood samples and tumor samples were collected from participants in the intervention arm; no blood was collected in the control arm, but DNA from cells in the mouth and tumor samples, if cancer arose, were collected for these participants.
   
   
9. What studies are being done with the collected information?
   PLCO investigators have completed and are carrying out hundreds of analyses from study data.  Published papers are available via scientific databases and a bibliography can be viewed online at http://www.parplco.org.
   
   
10. Can investigators who are not already part of the PLCO use this data for research?
    Yes. The Etiology and Early Marker Study program was created to allow non-PLCO researchers access to specimens and associated information from the trial.  Researchers must apply to use the resources and information, and approval of the application does not include funding of the project.  For more information, visit http://prevention.cancer.gov/plco/eems.  The clinical trial data will be available on another web page on or about October 1, 2012.
    
    
11. Can you give examples of the kind of research that uses data and specimens from PLCO?
    Following is a list of some of the most cited research using PLCO specimens and data:
    

    Author Year Journal	Title	Key Findings
    Cramer, D.W. et al 2011 Cancer Prevention Research	Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimens	This study showed that despite many promising new markers for ovarian cancer, CA-125 remains the single-best biomarker in the phase II and phase III specimens tested in this study.
    Caporaso, N, et al 2009 PLoS ONE	Genome-wide and candidate gene association study of cigarette smoking behaviors.	This study provides independent replication of the association between the chr15q25.1 region and smoking intensity and data for multiple other loci associated with smoking behavior.
    Landgren, O, et al  2009 New England Journal of Medicine	B-cell clones as early markers for chronic lymphocytic leukemia	In peripheral blood obtained up to 77 months before a CLL diagnosis, pre-diagnostic B-cell clones were present in 44 of 45 patients with CLL.
    Landgren, O, et al 2009 Blood	Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: A prospective study	Using pre-diagnostic longitudinal serum samples obtained 2 to 9.8 years prior to MM diagnosis, this study showed that an asymptomatic MGUS stage consistently preceded MM.
    Thomas, G. et al 2008 Nature Genetics	Multiple loci identified in a genome-wide association study of prostate cancer	Identified multiple loci with moderate effects associated with susceptibility to prostate cancer
    Ahn, J. et al 2008 Journal of the National Cancer Institute	Serum vitamin D concentration and prostate cancer risk: A nested case-control study	The findings do not support the hypothesis that vitamin D is associated with decreased risk of prostate cancer; higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease.
    Freedman, DM et al, 2008 Cancer Epidemiology Biomarkers and Prevention	Serum levels of vitamin D metabolites and breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial	This study did not observe an inverse association between circulating 25(OH)D or 1,25(OH)2D and breast cancer risk.
    Peters, U. et al 2007 Cancer Epidemiology Biomarkers and Prevention	Serum lycopene, other carotenoids, and prostate cancer risk: A nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial	This study showed that high serum beta-carotene concentrations were associated with increased risk for aggressive, clinically relevant prostate cancer. Lycopene and other carotenoids were unrelated to prostate cancer.
    Kang, D. et al 2007 Cancer Epidemiology Biomarkers and Prevention	Functional variant of manganese superoxide dismutase (SOD2 V16A) polymorphism is associated with prostate cancer risk in the prostate, lung, colorectal, and ovarian cancer study	Results from this study suggest that the Ala variant of SOD2 is associated with moderately increased risk of prostate cancer, particularly among men with lower intakes of dietary and supplemental vitamin E.
    Peters, U. et al 2004 Cancer Epidemiology Biomarkers and Prevention	Circulating vitamin D metabolites, polymorphism in vitamin D receptor, and colorectal adenoma risk	Higher serum 25(OH)D levels were associated with decreased adenoma risk. Serum 1,25(OH)2D and VDR TaqI genotype were not associated with adenoma risk.

    
    
12. Is the PLCO completed?
    No. There is continued follow-up of participants to strengthen the PLCO as a valuable resource for molecular epidemiologic research as well as provide long-term data on the trial’s primary endpoints. There will be at least an additional five years of annual active follow-up for those participants who agreed to collection of additional data, including medication use and medical conditions that are common among older adults; and collection of additional clinical data and tumor tissue for colorectal cancers. This five-year extension will strengthen the trial’s ability to clarify the long-term effects of screening on cancer mortality, and provide an opportunity to collect additional exposure data and expand the existing pathology tissue resource within the PLCO. PLCO participant follow-up is being done by a centralized administration rather than by each center.
    
    
13. Where can I find up-to-date information on the PLCO?
    Please visit the PLCO website at http://prevention.cancer.gov/plco.
    

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