The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial is a randomized, controlled trial of screening tests for prostate, lung, colorectal and ovarian cancers. Approximately 155,000 participants were enrolled between November 1993 and July 2001. Participants were individually randomized to the control arm or intervention arm in equal proportions. Participants assigned to the control arm received usual care, whereas participants assigned to the intervention arm were invited to receive screening exams for prostate, lung, colorectal and ovarian cancers as outlined in the study protocol. The goal of the study was to assess whether these screening exams reduce mortality from prostate, lung, colorectal and ovarian cancers. Data were collected on cancer diagnoses through 2009 (median follow-up time 11.3 years) and mortality through 2018 (median-follow-up 19.2 years). The ClinicalTrials.gov numbers for PLCO are NCT00002540, NCT01696968, NCT01696981, and NCT01696994.
Recruitment and Enrollment
Ten PLCO Screening Centers across the U.S. recruited possible participants and evaluated their eligibility to participate in PLCO. Nine of the ten centers began enrollment in November 1993. The tenth center began enrollment in January 1998.
Potential participants were excluded for the following reasons:
- Less than 60 years of age or greater than 74 years of age. Starting in January 1996, participants were excluded if they were less than 55 years of age or greater than 74 years of age.
- A history of prostate, lung, colorectal or ovarian cancer.
- Current treatment for any cancer except basal or squamous cell skin cancer.
- Prior surgical removal of the entire prostate, entire colon, or one lung.
- Prior surgical removal of both ovaries. Starting in October 1996, these women were no longer excluded.
- Starting in April 1995, males with more than one prostate specific antigen (PSA) test in the three years prior to enrollment.
- Starting in April 1995, participants with a colonoscopy, sigmoidoscopy, or barium enema in the three years prior to enrollment.
- Individuals who were participating in another cancer screening or cancer primary prevention trial.
- Males who have taken Proscar/Propecia/finasteride in the 6 months prior to randomization.
- Women who have taken Tamoxifen or Evista/Raloxifene in the 6 months prior to randomization. Starting in April 1999, these women were no longer excluded.
In order to be considered eligible for the study, participants also had to sign a consent form. Seven of the PLCO Screening Centers used a single consent approach, obtaining consent for all trial activities prior to randomization. The other three PLCO Screening Centers initially used a dual consent approach in which two consent forms were used. The first was administered to all participants before randomization for the baseline questionnaire and follow-up for cancer incidence and vital status. The second consent form was a "screening" consent administered to intervention arm participants after they were randomized. The dual consent approach appeared to lower screening compliance. The PLCO Screening Centers using dual consent phased out this approach in favor of single consent by December 1997.
Participants who met the eligibility criteria were randomized into the intervention and control arms. Randomization was stratified by age and gender within each screening center. The date of randomization was considered the official date of entry to the trial.
All participants were asked to complete a baseline questionnaire (BQ) containing baseline information such as demographics and medical history. Intervention arm participants were also asked to complete the Dietary Questionnaire (DQX) at baseline. A second dietary questionnaire-the Dietary History Questionnaire (DHQ)-was introduced in December 1998. The DHQ was administered to control arm participants at T0 and intervention arm participants at T3. Participants who had already passed these windows received the DHQ at their randomization anniversary in either 1999 or 2000.
Intervention arm participants were offered screening exams designed to detect P,L,C,O cancer. Men received a blood draw for the prostate specific antigen (PSA) exam to detect prostate cancer. Women received a blood draw for the cancer antigen 125 (CA-125) exam to detect ovarian cancer. The blood draw was usually performed prior to the other exams. Men received a digital rectal examination (DRE) to detect prostate cancer. Women received a transvaginal ultrasound (TVU) to detect ovarian cancer. Men and women were given a postero-anterior chest x-ray (XRY) to detect lung cancer. Men and women received a flexible sigmoidoscopy (FSG) to detect colorectal cancer.
The table below outlines the screening exam schedule. There were a number of screening protocol changes that took place in 1998 and 1999. "Never smokers" were no longer offered a T3 XRY exam, though those who insisted on it could still receive it. Participants were no longer offered their second FSG at T3 but instead at T5. Males were offered additional PSA screenings at T4 and T5. Females were offered additional CA-125 screenings at T4 and T5.
|Chest radiograph (XRY)||X||X||X||X1|
|Flexible sigmoidoscopy (FSG)||X||X2||X2|
|Males: Prostate specific antigen (PSA)||X||X||X||X||X3||X3|
|Males: Digital rectal examination (DRE)||X||X||X||X|
|Females: Cancer antigen 125 (CA-125)||X||X||X||X||X4||X4|
|Females: Transvaginal ultrasound (TVU)||X||X||X||X|
- Starting in December 1998, "never smokers" were no longer offered a T3 XRY exam.
- Starting in December 1998, participants were no longer offered a T3 FSG exam. Participants were offered a T5 FSG starting in October 1999.
- Males were offered a PSA at T4 and T5 starting in June 1999.
- Females were offered a CA-125 at T4 and T5 starting in June 1999.
In addition to the reasons noted above, intervention participants were not expected to undergo one or more of the annual screening exams if any of the following conditions were met:
- PLCO cancer reported
- A participant who reported a primary or metastatic cancer of the prostate, lung, colon, rectum or ovary, was not expected to undergo the screening examination(s) for that cancer.
- PLCO organ removal
- Prostate: Men who reported radical prostatectomy after entrance into the study were not offered a PSA or DRE exam.
- Colorectal: If the total colon was removed, the FSG examination was not offered.
- Ovarian: Women who have had both ovaries completely removed were not offered a CA-125 or TVU exam.
- Lung: Contrary to the organ removal protocol for the other PLCO sites, if a participant has had a lung either partially or completely removed, and the removal was not a follow-up to lung cancer, the chest X-ray was offered in all study years.
- Colonoscopic monitoring
- If a participant had an adenoma diagnosed after the initial screening exam, they were expected to receive additional follow-up colonoscopies depending on the standard of care in their community. If the screening center determined that the participant received follow-up colonoscopies, the second FSG screening exam was not offered.
Positive Screening Exams
Positive screening results were defined by the study protocol. The criteria for a positive screening exam are included in the table below.
|Screening Exam||Definition of a Positive Screen|
|XRY||One or more of the following: nodule, mass, hilar or mediastinal lymph node enlargement, infiltrate, consolidation, or alveolar opacity.|
|FSG||One or more of the following: rectal nodule, rectal and/or colon mass, colon polyp.|
|PSA||> 4 ng/mL|
|DRE||One or more of the following: nodularity, induration, asymmetry, loss of anatomic landmarks.|
|CA-125||≥ 35 U/mL|
|TVU||One or more of the following findings: ovary or cyst > 10 cc; solid area, or papillary projection extending into the cavity of a cystic ovarian tumor of any size; mixed (solid/cystic) component within a cystic ovarian tumor.|
A participant and his or her physician were notified of positive screening results. In the case of a positive FSG, it was standard practice not to biopsy or remove polyps or masses; instead, a referral was made to the participant's physician for diagnostic evaluation and follow-up.
Letters were mailed to participants and their health care providers usually within three weeks of an exam. Participants who had received a positive screening result were encouraged to receive a diagnostic evaluation. Participants and their physicians decided which procedures would be performed.
Medical Record Abstraction of P,L,C,O and non-P,L,C,O Cancers
For every cancer that was ascertained, information on cancer diagnosis was collected and recorded on the appropriate medical record abstract form. For non-P,L,C,O cancers, the cancer diagnosis date and ICD-O-2 code were collected. For every case of primary P,L,C,O cancer ascertained, additional information on diagnostic procedures; cancer stage, grade, and histopathologic type; and initial cancer treatment was recorded.
The vast majority of participants were followed until death or study termination, whichever came first. Participant withdrawal from the trial was rare and occurred for several reasons. Some participants refused further participation and communicated this to the PLCO Screening Center. A very small subset of these participants even withdrew consent to participate in the PLCO trial, and all their data were removed from the trial database. Other participants could not be located by the PLCO Screening Center for an extended period of time, so further attempts at follow-up were discontinued by the center. Others stopped participation due to medical problems or cognitive impairment.
The primary trial endpoints were cause-specific prostate, lung, colorectal and ovarian cancer mortality. To assess these endpoints, data were collected on all deaths (from any cause) that were known to have occurred during the trial. The main sources by which trial personnel learned of participants' deaths were (1) the administration of the Annual Study Update (ASU) questionnaires, (2) reports from relatives, friends, or physicians, and (3) National Death Index (NDI) Plus searches. After notification, PLCO Screening Centers attempted to obtain a death certificate for each death that occurred on or before December 31, 2009. Information from the death certificate was coded and recorded in the trial database. The underlying cause of death from death certificate was derived according to rules established by the National Center for Health Statistics. In order to provide a more accurate assessment of the trial endpoints, a Death Review Process (DRP) was conducted and medical records were reviewed for all deaths that might have been due to P,L,C,O cancers. The DRP cause of death was considered authoritative and was used in statistical analyses of the primary endpoints.
Results of Study
For a list of PLCO publications, see the PLCO Main Findings section.
As blood was obtained for the CA-125 and PSA screens in the intervention arm, additional samples were collected for research. Buccal cells were collected for the control arm. Tumor tissue was collected for tumors diagnosed during the trial. These biospecimens are stored at the PLCO Biorepository in Frederick, Maryland. For more information on the materials available, the protocol of collection and the approval process for acquisition see the PLCO Biospecimens Collected section.
In 2009 the NCI decided to expand data collection on PLCO participants beyond the initial study design in order to acquire more cancer outcomes and continue to track mortality. This required the remaining PLCO participants to be contacted and reconsented. At the time of this effort, ~31,000 participants were dead, ~5,000 participants were lost to active follow-up but were being followed passively, and <500 participants had chosen to withdraw from the trial, leaving ~118,000 participants needing to be reconsented. The outcome of the reconsenting was that ~83,500 participants chose to continue actively participating in the trial, ~16,000 additional participants became followed passively, and ~18,000 participants declined to be part of the extended follow-up. This results in final populations of ~83,500 active participants who were willing to continue study activities, ~21,000 participants who were passively followed, and a total of ~136,000 participants (active, passive, or dead) who were eligible for additional linkages with cancer registries and the National Death Index.