Is aggressive treatment really indicated for mild Pap test abnormalities?
Is aggressive treatment really indicated for mild Pap test abnormalities?
NCI study uses new technology to reduce number of inconclusive results
The Rockville, MD-based National Cancer Institute (NCI) is launching a national clinical trial to resolve one of the thorniest questions in women’s health care: How aggressively should providers treat the low-grade abnormalities that show up on as many as 10% of all Pap tests performed in the United States?
About 50 million Pap smears are performed in the United States every year, according to the NCI. Serious, precancerous abnormalities, called high-grade squamous intraepithelial lesions (HSIL), appear in about 300,000 women and are routinely treated through surgery. No consensus exists, however, on how to treat milder abnormalities, called atypical squamous cells of undetermined significance (ASCUS), says Diane Solomon, MD, senior investigator at the NCI and one of the trial’s project officers. (For a breakdown of Pap test abnormalities by diagnosis, see p. 54.)
"We know that a majority of these sorts of minor low-grade abnormalities either go away on their own or will not get any worse," says Solomon. "The only reason we’re [aggressively] treating women who have them is that a small minority of them either have a higher-grade lesion that’s underdiagnosed or have a potential to progress to a higher-grade lesion. So, in a sense, you end up overtreating the majority of women who have lesions that really are not of clinical concern in order to be sure you don’t miss the minority who have the potential of greater risk."
Examining women with ASCUS results surgically by means of a colposcopy, in which the physician examines the cervix and biopsies any abnormal areas costs about $1,200 per case. That adds up to a total annual cost of about $3.6 billion per year, according to the NCI. Cost factors, the possibility of complications from surgical intervention, and heightened patient anxiety over acute treatment have led NCI researchers to study whether aggressive surgical treatment of women with ASCUS results is really appropriate, says Solomon.
The ASCUS/LSIL Triage Study (ALTS) will enroll and provide follow-up care to about 7,200 women at four different clinical centers in the United States. The women, all with a recent diagnosis of ASCUS or LSIL (low-grade squamous intraepithelial lesions), will be assigned to one of three different management groups and tracked for about three years. The management groups include the following: (For a graphical representation of the study, see p. 55.)
• Immediate colposcopy.
Women in this group will be given the current standard management approach. They will receive a colposcopic examination and biopsy of all possible lesions.
• Conservative management.
Women assigned to this group will be followed closely with repeat Pap tests every six months, a standard approach in Canada and certain European countries. If follow-up tests suggest the presence of high-grade lesions, patients will undergo colposcopy and biopsy.
• HPV triage.
Patients will be tested, based on the results of the Pap test, for certain types of human papillomaviruses (HPV), as a way to differentiate between abnormalities that require immediate colposcopy and those that can be managed more conservatively.
Women in the ALTS study will be monitored not by means of the traditional Pap test but with a new test called the ThinPrep 2000 the first liquid-based test to be approved by the U.S. Food and Drug Administration.
Although the conventional 50-year old Pap test has proven successful in lowering the rate of cervical cancer, some treatment centers have switched to ThinPrep in light of the troubling possibility that the older test may not be completely accurate. About half of all missed abnormalities result from inadequate specimen collection under the conventional test, according to the NCI. The other half result from a failure to identify the abnormal cells or to interpret them accurately, the NCI contends. Indeed, recent studies suggest that anywhere from 6% to 55% of all slides are read incorrectly, says Vincent Lucente, MD, chief of gynecology for the department of obstetrics and gynecology at Lehigh Valley Hospital and Health Network (LVH) in Lehigh Valley, PA.
Developed by the Boxborough, MA-based Cytyc Corporation, ThinPrep eliminates most of the problems physicians have traditionally had with Pap smears, says John Shane, MD, chairman of pathology at LVH. For example, with conventional Pap smears, up to 80% of the collected cells are discarded with the collection device. Also, an unacceptably high number of all smears are tainted by mucus obscuration, red blood cell obscuration, inflammation, and poor preservation, says Shane. "And each inadequate or less than adequate specimen triggers a repeat test, which brings the patient back for another visit," Shane adds. "And it costs another Pap smear."
With the conventional Pap smear test, the provider manually smears a small portion of the cervical cells onto a slide. With the ThinPrep test, the provider rinses the collection device in a vial of preservative solution. He or she then sends the specimen to a laboratory, where a processor filters it to reduce blood, mucus, and inflammation. The processor also evenly disperses the specimen and applies a thin layer of the cervical cells to a slide.
"The advantage of the ThinPrep is that, first of all, you have a total and even dispersion of cells in the collection medium that winds up on the slide," says Shane. "It could be that in the 80% of the cells that get discarded [with the conventional Pap test], the endocervical cells are among those that end up in the waste basket. Because it’s not a homogeneous dispersion of cells, you may not have the cells you want to see winding up on the slide."
Solomon adds that according to recent data "there is a suggestion that with this technology, there are fewer ASCUS cases because there’s better fixation. You don’t have the problems of interpretation that you sometimes have with the conventional smear."
"Basically, by using a better test, you’re reporting a more reliable result," says Shane. "You’re going from 5% to 10% indeterminate results to 1% to 2% indeterminate. That allows you to give your patient a more accurate and dependable result, which serves to eliminate all the anxiety and inconvenience of repeats. You also eliminate all the unnecessary surgical intervention for repeat indeterminate smears, for which your only way to get a definitive answer by routine Pap technique is to go ahead and get a surgical biopsy."
Liquid-based cytology has already won over physicians and staff at LVH because it simplifies the collection process, says Shane. "They just use the collection device, drop it in a vial, put the cap on, roll it around a couple of times, and send it to the lab," he says. "They don’t have to have someone in their office smearing the slides up, spraying them, letting them dry, then packaging the slides. In terms of the doctor’s office, it’s more convenient than the old technology."
Although some insurance companies have "enthusiastically espoused" the new technology, others have been slower to accept the ThinPrep test, largely because it costs more than the traditional Pap smear, concedes David Beckwith, PhD, vice president and clinical director of Network Laboratory Services at LVH.
The collection vial used for the ThinPrep test costs $9, with no reduction in price for volume buying. In addition, the processors that ThinPrep requires cost $40,000 each. "It’s probably at least tenfold more expensive than the conventional methodology," Beckwith says.
Shane adds that LVH’s laboratories process about 30,000 Pap tests per year. The labs have two processors to handle the load, each with a life expectancy of between three and five years. "In three years, we’re going to be doing 90,000 specimens. So you wind up with an equipment cost of about a buck a piece. Add in $9 for a collection vial for each specimen, and it costs you an additional $10 per specimen [to use ThinPrep]."
Nevertheless, the added efficiency of the ThinPrep system allows staff to conduct a greater number of screenings, says Shane. "So, on one hand, you have increased cost of equipment and supplies. On the other hand, you have decreased personnel costs and increased productivity," he says. "Let’s not kid ourselves. The test is going to be more expensive to do. But if you balance it with fewer repeats, fewer colposcopies and biopsies, then it begins to make sense."
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