The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, or PLCO, is a large-scale clinical trial to determine whether certain cancer screening tests reduce deaths from these cancers. Screening for cancer may enable doctors to discover and successfully treat the disease earlier, preventing deaths. Numerous epidemiologic and other studies are also part of the research.

Sponsored and run by the National Cancer Institute's Division of Cancer Prevention, the PLCO trial is taking place at 10 Screening Centers across the country: Denver, Colo.; Washington, D.C.; Honolulu, Hawaii; Detroit, Mich.; Minneapolis, Minn.; St. Louis, Mo.; Pittsburgh, Pa.; Salt Lake City, Utah; and Marshfield, Wis.

Between 1993, when the trial opened and 2001, when enrollment was completed, 154,942 women and men between the ages of 55 and 74 joined PLCO. Screening of participants with annual exams will continue until 2006. Additional follow-up will continue for up to eight more years to determine the benefits or harms of the cancer screening exams being studied.

The PLCO Trial also includes research on the genetic and environmental causes of cancer (prostate, lung, colorectal, ovarian, and other types of cancer) and studies of new methods for the early detection of cancer in collaboration with the NCI's Division of Cancer Epidemiology and Genetics.

Together, these four cancers account for 42 percent of all diagnosed cancers in the United States and nearly half of all cancer deaths (47 percent). An estimated 266,360 people will die of prostate, lung, colorectal and ovarian cancers in 2005.

Background on Prostate Cancer

Based on current U.S. rates, about 18 of every 100 men born today will be diagnosed with prostate cancer in their lifetime, while about 3 of every 100 men will die from this disease.

Although prostate cancer can occur in men of all age, more than 70 percent of cases are in men over the age of 65. Men are at greater risk if prostate cancer runs in their family, especially if a father or brother has had the disease. African-American men are also at increased risk of prostate cancer, although researchers are not sure of the reasons. Some studies have shown that a diet high in fat may also increase risk.

In the PLCO Trial, researchers are studying whether a digital rectal exam (DRE) plus a blood test for prostate-specific antigen (PSA) will decrease deaths due to prostate cancer. A DRE is a physical exam where a health professional feels for abnormalities in the prostate gland. Because the prostate is located near the rectum, it can be felt by inserting a gloved finger into the rectum.

PSA is a protein produced by prostate cells and PSA levels frequently are elevated in the blood of men with prostate cancer. The Food and Drug Administration (FDA) approved PSA screening for monitoring patients after prostate cancer treatment and for detection of prostate cancer in conjunction with DRE in men age 50 or over. However, it is still unknown whether PSA screening alone, or in combination with DRE, leads to a reduction in prostate cancer death.

Patient Population and Trial Design

The PLCO is a randomized, controlled trial in which over 150,000 persons 55 to 74 years old at entry were randomized to two study arms, half to undergo cancer screening (intervention group) and half to continue their normal health care routine (control group). Both groups answer yearly questionnaires about their health.

The 38,000 men in the intervention group undergo annual screening for prostate cancer with PSA screening and DRE. They also undergo screening for colorectal cancer (flexible sigmoidoscopy) and lung cancer (chest radiograph). The primary objective of the prostate component of the PLCO trial is to determine, in men age 55 to 74 years old at entry, whether screening with DRE plus serum PSA can decrease mortality from prostate cancer.

If a participant has a positive result from a screening test, the results are shared with the participant and his physician or a referral to an appropriate physician is made. The PLCO Trial design does not dictate the type of follow-up a person should have, although information on follow-up tests is collected.

Data Collection

Men in the screening arm of this trial undergo PSA testing and DRE upon entry. The men then have these tests annually for the next three years, and then have a PSA test without DRE in years 4 and 5. All PSA levels are analyzed by a single laboratory to ensure the quality and consistency of the results. Participants in the intervention and control groups are contacted yearly for 13 years from the time they enter the study in order for the researchers to monitor their health.

Results/Publications

The following PLCO analyses regarding prostate cancer have been published, with the most recent studies listed first:

• The PLCO trial is evaluating PSA- and DRE-based screening for prostate cancer in a clinically valid manner. Results of the baseline round of prostate cancer screening in the PLCO trial show about 14 percent of men had either a positive PSA test or a positive DRE test. Of those men, about 12 percent were diagnosed with prostate cancer within 12 months, the majority with early stage disease. The impact on prostate cancer deaths cannot yet be measured.

A total of 38,350 men were randomly assigned to the intervention arm of the PLCO trial. At the time of enrollment, all age groups were well represented, with higher proportions of men in the younger age groups. Compliance rates among the men for PSA and DRE were roughly 89 percent. The results of the screening tests showed that 7.5 percent of the study participants had a positive DRE and 7.9 percent had a positive PSA. Of these men, 74 percent proceeded to have further diagnostic evaluation and 31.5 percent underwent a biopsy of the prostate within one year of the positive screening test. A total of 556 of 4,801 men who showed suspicious screening results were diagnosed with prostate cancer within one year of the positive screen. Overall, 83 percent of the men who were diagnosed with prostate cancer were diagnosed with Stage I or II cancer without spread to lymph nodes or other organs.

The study results differ from those of some other studies mainly with respect to the percentage of men with positive screens undergoing biopsy and the overall prostate cancer yield. The higher detection rate in those studies compared to the initial round of the PLCO trial may be related to their higher biopsy rates. The difference in biopsy rates is to be expected given the different study designs. The question of change in prostate cancer mortality as a result of screening cannot be answered at this early stage in the PLCO trial.

Reference: Andriole GL, Levin DL, et a. "Prostate Cancer Screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial: Findings from the Initial Screening Round of a Randomized Trial." Journal of the National Cancer Institute. Vol. 97, No. 6. March 16, 2005.

• Men who receive a reproducible prostate specific antigen (PSA) test result of 7 ng/ml (nanograms per milliliter) or greater are more likely to have a subsequent prostate biopsy compared to men with lower but still abnormal test results. The results were measured over three years. Men with a positive digital rectal exam (DRE) without a positive PSA test were less likely to receive biopsy than men with a positive PSA test.

A total of 4,801 out of close to 40,000 men who were originally randomized to the screening arm of the PLCO trial had one abnormal prostate screening test upon entry, including 2,717 with abnormal PSA levels. The results of a PSA test or DRE had a substantial impact on biopsy rates:

• Men with PSAs greater than 4 ng/ml (considered positive in this study) upon entry into the PLCO trial had a biopsy rate over a three year period of 64 percent, while those with a positive DRE and PSA of 4 ng/ml or less had a 27 percent biopsy rate.
• Men with a baseline PSA greater than 10 ng/ml had a greater biopsy rate (85 percent) after three years that did men with baseline PSAs of 4 to 7 ng/ml (58 percent).
• Among men first becoming PSA positive (greater than 4 ng/ml) after the study entry screen, those with PSA levels greater than 10 ng/ml were not more likely to receive a biopsy than men with PSAs of 4 to 7 ng/ml.

The study authors were able to identify various factors that affected biopsy rates:

• Prior prostate biopsy, prior PSA tests, and a history of prostate problems were significantly associated with a lower biopsy rate only in men whose PSA was positive at entry.
• In men with a positive DRE and negative PSA, a PSA value of 2.5 to 4.0 ng/ml was associated with an increased biopsy rate compared to a result lower than 2.5 ng/ml.
• Among men with a PSA test greater than 4 ng/ml, men with a positive DRE were about twice as likely to receive biopsy as men with a negative DRE.
• Men often got repeat PSA screening after the initial screening PSA. Those with repeat PSAs below 4ng/ml had much lower biopsy rates than men with repeat PSAs greater than 4 ng/ml.

Reference: Pinsky PF, Andriole GL, et al. "Prostate Biopsy Following a Positive Screen in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial." Journal of Urology. Vol. 173. March, 2005.

• A man's willingness to continue having prostate cancer screening tests is affected by a false-positive result on a previous prostate cancer screening and other measures. Men were significantly less likely to continue prostate cancer screening following a false-positive prostate cancer screening result. Other significant predictors of not receiving further prostate cancer screening were African-American race and having less than a high school education.

The purpose of this study, conducted at the Henry Ford Health System site in Detroit, Mich., was to examine factors affecting compliance with future prostate cancer screening tests. The data were drawn from the PLCO Cancer Screening Trial consisting of 2,290 older men (mean age, 62.8 years; range 55-75 years) who had a negative or false-positive prostate-specific antigen test or digital rectal exam at baseline.

The study points to a need to better understand health decision-making processes for people receiving a previous false-positive prostate cancer screening result. During shared decision-making processes, patients' attitudes and perceptions of the false-positive screening results could be ascertained, as well as patients' preferences for future prostate cancer screening behavior. This process could assist clinicians in ensuring that patients make informed choices about subsequent prostate cancer screening.

Reference: Ford ME, Havstad SL, et al. "Effects of False-Positive Prostate Cancer Screening Results on Subsequent Prostate Cancer Screening Behavior." Cancer Epidemiology, Biomarkers & Prevention. Vol. 14, No.1. January 2005.

• Many men who choose to get a prostate specific antigen (PSA) test may not need to repeat the test as frequently as previously thought.

These results from the PLCO Trial were presented in the general plenary session at the annual meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Fla, on Monday, May 20, 2002. PLCO researchers found that, in men with an initial PSA value between 0 to 1 ng/ml, 98.7 percent would continue to have PSA levels below 4 ng/ml through four additional years of PSA testing. For men with initial PSA readings of 1 to 2 ng/ml, investigators found that 98.8 percent would have a reading below 4 ng/ml the following year. For men with readings of 2 to 4 ng/ml, the chances that the PSA would rise to at least 4 ng/ml were higher.

Reference: Crawford ED, Chia D, et al. "PSA Testing Interval Reduction in Screening Intervals: Data from the Prostate, Lung, Colorectal and Ovarian (PLCO) Screening Trial." ASCO 38th Annual Meeting, Program/Proceedings 2002.

• In healthy male volunteers randomized to the screening arm within the PLCO Trial, race, age, and history of benign prostate disease are linked to variations in free (no longer bound to protein) and total (bound and unbound) PSA, but not percent free PSA. The differences are small and are of limited use in the clinical setting. However, since percent free PSA does not seem to be affected by race, this measurement may be useful when making comparisons across diverse groups.

A sample of 7,183 men randomized to the intervention arm of PLCO between 1993 and 1997 was included in this ancillary study of free and total PSA. To maximize minority participation, all non-white and Hispanic men randomized by 1997 were included in the selection. Blood drawn at the initial visit of these participants was measured for both total PSA and free PSA levels. Median levels of serum PSA were less than 2.1 ng/ml for all age-race groups. Free and total PSA were higher in blacks than whites and Asians. Hispanic men had median PSA levels higher than non-Hispanic whites. Free and total PSA levels increased with age, particularly men 70-74 years old. The differences in percent free PSA across age and race groups were smaller than the differences in total PSA and in free PSA. Regardless of race, men with a history of benign prostate diseases had higher free and total PSA levels.

Reference: Gelmann EP, Chia D, et al. "Relationship of Demographic and Clinical Factors to Free and Total Prostate-Specific Antigen." Urology Vol. 58 , No. 4. May 2001.