Key Points 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 death from cancer. In 2005 in the United States, it is estimated that 22,200 women will be diagnosed with ovarian cancer resulting in 16,200 deaths, making ovarian cancer the fourth leading cause of cancer deaths in women. Current screening tests for ovarian cancer include bimanual palpation, CA-125, and TVU.

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 death from cancer. The PLCO is testing the effectiveness of early prostate, lung, colorectal, and ovarian cancer detection using the following tests: digital rectal examination and blood prostate-specific antigen (PSA) testing for prostate cancer, chest X-ray for lung cancer, flexible sigmoidoscopy for colorectal cancer, and transvaginal ultrasound (TVU) and the blood cancer antigen (CA)-125 for ovarian cancer. 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: Birmingham, Ala.; 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 will continue until 2006. Additional follow-up will continue for at least 10 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 (PLCO and other types of cancer) and studies of new methods for the early detection of cancer, in collaboration with the National Cancer Institute's Division of Cancer Epidemiology and Genetics.

Together, prostate, lung, colorectal, and ovarian 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 cancer in 2005.

Background on Ovarian Cancer:

In 2005 in the United States, it is estimated that ovarian cancer will be diagnosed in 22,220 women and result in 16,200 deaths. Ovarian cancer is the fourth leading cause of cancer death in women. Although ovarian cancer accounts for about 4 percent of all cancers in women, it has the highest mortality of all gynecologic cancers because it is often diagnosed at an advanced stage. This is due to a lack of early symptoms and proven screening tests. Long-term survival is achieved in less than a third of patients.

Current screening tests include bimanual palpation, CA-125, and TVU. Feeling the ovaries during a pelvic exam is a widely used technique but it is not sensitive enough to detect early-stage cancer. CA-125 is a test that measures the level of cancer antigen 125, a sugar protein in the blood. Often this protein is released when cells are inflamed or damaged. Increased levels of CA-125 can be a sign of cancer. TVU is a procedure that uses sound waves to examine the vagina, uterus, fallopian tubes, ovaries, and bladder for abnormalities.

Patient Population, Trial Design, and Data Collection in the PLCO:

The PLCO is a randomized, controlled trial in which over 150,000 people 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 first ovarian cancer screening tests were performed on the first participant on November 15, 1993.

The 39,115 women in the intervention arm are screened for ovarian cancer using CA-125 annually six times and TVU annually four times. Originally, feeling the ovaries during a physical exam was included in the protocol, but the procedure was dropped in 1998 after review of the data revealed that no ovarian cancers had been detected with this procedure alone. The primary objective of the ovarian component of the PLCO trial is to determine in women, age 55 to 74 years old at entry, whether screening with CA-125 and TVU can decrease mortality from ovarian cancer.

If a participant has a positive result from a screening test, the results are shared with the participant and her 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. Participants in the intervention and control groups will be followed for at least 13 years from the time they enter the study.

Results/Publications:

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

Screening and Related Clinical Studies-

• In the first year of screening in the PLCO Trial, CA-125 and TVU were able to identify both early- and late-stage ovarian cancers, but the ability of these tests to accurately predict the presence of the disease was relatively low. The effect that screening for ovarian cancer has on mortality in the PLCO population is still unclear and will require longer follow-up.

This paper summarizes initial data gathered from baseline screenings, the initial tests performed when patients were first enrolled in the trial. Of the 28,816 women screened, 29 tumors were detected. Twenty of these tumors were invasive, and nine were tumors of low malignant potential. The tumors were identified among 1,338 women who had an abnormal TVU and 402 women who had an abnormal CA-125 test.

The positive predictive value of these tests for invasive cancer was 3.7 percent for an abnormal CA-125 test, 1 percent for an abnormal TVU, and 23.5 percent if both tests were abnormal. The authors recommend that no changes be made to the current ovarian cancer screening guidelines of the US Preventive Services Task Force. These guidelines, from 1996, state that "routine screening for ovarian cancer by ultrasound, the measurement of serum tumor markers, or pelvic examination is not recommended." Since this recommendation is based on data from only the first year of data from the trial, future follow-up will offer more information on the effectiveness of these screening tests to prevent mortality from ovarian cancer.

Reference: Buys SS, Partridge E, et al. "Ovarian Cancer Screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial: Findings from the Initial Screen of a Randomized Trial." American Journal of Obstetrics and Gynecology, November 15, 2005.

Studies of Cancer Causes

• In postmenopausal women, complex ovarian cysts, which have multiple compartments, do not appear to be the immediate precursors of ovarian cancer. Also, these cysts are not associated with other ovarian cancer risk factors, such as family history of ovarian or breast cancers.

Precursors to ovarian cancer have yet to be identified, but possible candidates are non-malignant ovarian abnormalities like cysts that are detected by TVU in symptom-free postmenopausal women. If these abnormalities were cancer precursors, they would be found more often in women with established risk factors for ovarian cancer.

Researchers compared TVU findings from 20,000 postmenopausal women and compiled data on their risk factors from participant questionnaires filled out when the women were enrolled in the PLCO study. Researchers found that complex ovarian cysts were less prevalent in women who had more children but were unrelated to oral contraceptive use, both strong ovarian cancer protective factors. Prevalence of cysts was unrelated to a woman's age or family cancer history, both strong risk factors for ovarian cancer. This study suggests that complex ovarian cysts are not precursors of ovarian cancer in postmenopausal women.

Reference: Hartge P, Hayes R, et al. "Complex ovarian cysts in postmenopausal women are not associated with ovarian cancer risk factors." American Journal of Obstetrics and Gynecology. 183(5):1232-1237. November 2000.

For more information about cancer, visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4 CANCER (1-800-422-6237).

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