BETHESDA-A small but vocal group of clinical researchers wants to scrap the world’s biggest cancer-screening trial.   These critics say the National Cancer Institute’s $160-million study, the first to examine four cancers simultaneously, will answer nothing. At best, they allege, it will reaffirm the obvious benefits of sigmoidoscopy.   The critics say the study includes ovarian cancer only because the NCI tried to be politically correct. More important, they say technology is rapidly refining better tumor markers, and those tested now will be obsolete by the end of the trial. What’s more, PSA’s widely publicized growth has led to inevitable contamination in the control group. And there’s no control in the study for treatment.   The critics include some within NCI, almost fanatic in their vituperation, and others in academic medicine. Most would not be identified by name, fearing either job or grant retaliation. In all, the 16-year study aims to include 148,000 American men and women, ages 55 to 74, in 10 centers to find out whether screening makes a significant difference in mortality, the endpoint.   The trial was conceived in 1988 for prostate screening. Colon and lung were included as cost-effective adjuncts. Then Dr. Samuel Broder, NCI director at the time, insisted on including women, apparently to appease women’s health advocates miffed that most NCI trials were men-only. So ovarian screening was added, leading to a four-year delay in starting the trial, despite the unlikely possibility that CA-125 will be found effective as a mass-screening tool. The delay may have doomed the prostate part of the trial.   Called the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, or PLCO, it is already into its sixth year, with some 90,000 volunteers. All are randomized to x-rays for lung-cancer detection, the men to digital rectal and PSA for prostate cancer, and the women to transvaginal ultrasound and blood tests for CA-125 levels for ovarian cancer. For those randomized to flexible sigmoidoscopy, it is done on the initial visit and three years later.   Defenders say cancer-screening policy based on anything but a randomized trial is useless, and that lacking such a trial, policy will be based on hunches from observational data or case-control studies.   “When there are debates about whether screens work, the only way to resolve them is a randomized clinical trial,” says Dr. John Gohagan, a Ph.D. epidemiologist who heads NCI’s early-detection branch.   Dr. Charles Smart, his predecessor, says that 25 years of unsatisfactory trials of breast-cancer screening, seeking to find the optimum age for starting mammography, should have been a tipoff to the limitations of a PLCO-style study.   “It comes down to a philosophical approach to medicine,” says Dr. Barnett Kramer, deputy director of cancer prevention and control for NCI. “What level of evidence are you willing to accept? I would say when you have to make a blanket recommendation to the entire American public you want to have the strongest evidence in hand.” Yet he concedes that PLCO has many critics.   Surgeon LaMar McGinnis, a past president of the American Cancer Society, has been frustrated by slow patient accrual. That means “the likelihood of useful information emerging is not very good, particularly with science changing so rapidly,” he says.   But PLCO enthusiasts say the demand for speed has a politically expedient ring. And Dr. Gohagan says accrual isn’t lagging but merely that the original estimate was off target. He has requested two more years to complete enrollment. And to mollify those who say PSA’s sudden prominence during the four-year delay to achieve political correctness contaminated the prostate control group, the study excluded men who’d had PSA within the past three years.   Critics carp that a randomized trial tallying death rates after sigmoidoscopy is pointless because early detection is known to lower mortality for colon cancer. A speedier study showing the effectiveness of the technology in detecting colon cancer early is sufficient. Investigators retort that the colon part of the trial will be stopped as soon as evidence emerges that flexible sigmoidoscopy saves lives.   And CA-125, say critics, is not ready for testing. “We probably should be spending the money on developing better tests and not doing trials on interventions that are only modestly useful,” says Dr. Paul Engstrom of Philadelphia’s Fox Chase Cancer Center. Randomized trials work best with placebo-controlled treatment trials, he adds.   Yet policymakers rely on results of randomized trials. “To say that screening trials aren’t important flies in the face of the way policymakers behave,” says the University of Minnesota’s Dr. Jack Mandel, a PLCO investigator. “There’s no other way to evaluate screening tests. You can get estimates, but the consequences of being wrong are profound.”   Duke’s Dr. Barbara Rimer, soon to head up NCI’s division of cancer control, says that because of the size of the randomized screening trials and time needed to detect effects, the institute must take great care to be sure they’re done only for questions that can’t be answered any other way.   “To reduce contamination, we may be able to limit the studies to a high-risk group or to do them in countries where screening is not so popular,” she adds. “But the gold standard for determining reduction in mortality remains the randomized clinical trial.” -Randi Hutter Epstein