Feasibility of Management of High-Grade Cervical Lesions in a Single Visit:  A Randomized Controlled Trial FREE

Cervical cancer incidence rates in the United States have progressively declined because of the widespread application of cervical cancer screening and treatment of precancerous lesions. The majority of cervical cancers diagnosed in this country are among women who have never received a Papanicolaou test or who are noncompliant with screening and follow-up.¹ The incidence of cervical cancer is higher among low-income and minority women, Latinas in particular.^2- 3

The barriers to cervical cancer screening and management have been well described. They include poverty, lack of health insurance, limited transportation, language difficulties, lack of child care, lack of telephone access, and certain cultural-based attitudes and health behaviors.^4- 8 Low-income and minority women shoulder a disproportionate share of the cervical cancer burden in this country.⁹

We believe that the usual approach to cervical cancer screening, diagnosis, and management accentuates some of these barriers because it is cumbersome and expensive, ordinarily involving multiple clinic or hospital visits and requiring a period of months to complete. A particularly troublesome problem concerns the follow-up of abnormal Papanicolaou test results. Numerous authors have reported loss to follow-up rates between 20% and 50%.^10- 13 Therefore, it is important to evaluate new approaches that take advantage of more efficient screening methods that include the complete evaluation of an abnormal Papanicolaou test result and, thus, control this preventable cancer.

To address this problem, we developed an innovative cancer control program to simplify the approach to cervical screening and management of high-grade cervical dysplasia among predominantly Latina women from underserved communities. We hypothesized that women who received results and explanations about the importance of follow-up for an abnormal Papanicolaou test result on the same day as the test would be more likely to follow up.

Our objectives were to determine the feasibility and acceptability of treating high-grade abnormalities identified by Papanicolaou test in a single-visit cervical cancer screening and treatment program and to compare rates of definitive treatment within 6 months and follow-up rates 12 months later with those of women receiving usual care. A secondary aim was to compare the rates of definitive assessment or treatment and follow-up of women with lower-grade abnormal results.

Recruitment strategies have been previously described in detail.¹⁴ We provide a summary of the strategies herein. A pilot study testing the clinic protocol has also been published.¹⁵ The study was approved by the institutional review board of the University of California, Irvine (UCI).

For the first year of this study—January to December 1999—women were recruited from the UCI community health centers in Anaheim and Orange. These clinics are located in predominantly Latino underserved areas of Orange County. All women who had visited either of these clinics as a patient or guardian within the last 3 years were identified from the clinic registries. We invited these women to participate in the study using bilingual (English/Spanish) letters of introduction.

From January 2000 to April 2002, media recruitment strategy was predominantly used to enhance participation. This approach made use of advertisements in local community and regional newspapers, television, and radio. Additionally, fliers were distributed at health fairs and placed in local businesses and community centers. Women who wished to participate contacted bilingual study recruitment staff members, who screened them for eligibility. These 2 recruitment strategies, clinic registry and media campaign, yielded similar populations with respect to many important variables, such as income, education, employment status, interval since previous Papanicolaou test, history of an abnormal Papanicolaou test result, number of lifetime sexual partners, and age at first sexual intercourse.

Irrespective of the recruitment strategy, all eligible women were screened for eligibility by telephone in their preferred language. The randomization and study procedures were explained in detail to potential participants. All participants were made aware of the possibility of a 2- to 3-hour wait in the clinics. Oral consent was obtained from eligible patients who were then scheduled for a visit at 1 of the 2 study clinics.

Women were considered eligible to participate in this program if they were older than 18 years, had no history of invasive cervical cancer, and were not pregnant. Exclusion criteria included absence of a cervix, abnormal vaginal bleeding, cervical cancer screening within the previous 12 months, a known bleeding disorder, reluctance to be randomized, or unwillingness to follow the study protocol. Reasons for ineligibility or refusal to participate were documented. After written informed consent was obtained, the participants were randomized in blocks of 4 to 1 of 2 study groups, a usual care program or a single-visit program. Randomization assignment was completed by the statistician (A.Z.) using SAS software, version 9 (SAS Institute Inc, Cary, NC). The sequences generated were placed in envelopes and provided to the study coordinator, who allocated participants based on the order in which the patients registered in the clinic. The protocol stipulated that women would be excluded after randomization for a gross cervical lesion suspicious for malignancy at the time of examination.

Women randomized to the usual care group were discharged home immediately after the pelvic examination, conventional Papanicolaou test collection, and interview. Visit time for each patient was measured from the time of registration in the clinic until discharge. Participants were notified of their Papanicolaou test results by mail within 2 to 4 weeks. If the Papanicolaou test result was abnormal, the participant was also contacted by telephone and advised to seek additional evaluation of her cervical abnormality. If the participant had no identifiable primary care practitioner or gynecologist, a referral was made to the UCI gynecologic abnormal cytology clinic. A copy of the abnormal Papanicolaou test result was mailed to participants who planned to receive their follow-up outside the UCI medical system.

All women randomized to the single-visit group were expected to remain at the clinic until the results of their conventional Papanicolaou tests were available. As in the usual care group, visit time for each patient was measured from the time of registration in the clinic until discharge. The Papanicolaou test specimens of the women in the single-visit group were delivered by courier to the UCI pathology department, where they were immediately processed and interpreted by a single pathologist (F.L.). Cytologic evaluation was conducted according to the Bethesda system, and the results were orally communicated to the study nurse practitioner. However, for Papanicolaou test results indicative of a high-grade squamous intraepithelial lesion (HGSIL), atypical glandular cells of undetermined significance (AGUS), or carcinoma, the pathologist communicated directly with the study investigator (W.R.B.) and faxed a report to the clinic. Cervical loop electrosurgical excision procedure (LEEP) was offered to single-visit patients with these abnormal findings. LEEP was performed without colposcopy with removal of the transition zone. A separate endocervical excision was not part of the procedure. For single-visit patients with AGUS, an endometrial biopsy was performed prior to cervical LEEP. Patients who had cervical LEEP received discharge instructions to return twice, at 2 weeks and at 3 months, for follow-up. Single-visit patients with diagnoses of atypical squamous cells of undetermined significance (ASCUS) or a low-grade squamous intraepithelial lesion (LGSIL) were referred to either their primary care practitioner or the UCI gynecologic abnormal cytology clinic for additional evaluation and treatment. A copy of the Papanicolaou test report was mailed to all single-visit patients with abnormal Papanicolaou test results who intended to receive follow-up outside of the UCI medical system.

All participants completed questionnaires eliciting information related to medical history, demographic information, race and ethnicity classifications (determined by the participants), risk factors for cervical cancer, prior Papanicolaou tests, attitudes about cervical cancer screening and prevention, and barriers to health care. In addition, a self-administered satisfaction survey using a 5-point Likert scale was administered to participants in both the usual care and single-visit groups prior to discharge from the clinics. Each participant completed a self-addressed postcard that was mailed 12 months later to remind her to follow up for a free repeat conventional Papanicolaou test.

Usual care was expected to be representative of general care. Information on follow-up of usual care participants with abnormal Papanicolaou test results was obtained from the patients and medical records were reviewed. For usual care patients with Papanicolaou test results indicating HGSIL, a definitive evaluation, considered equivalent to the LEEP offered to single-visit patients, was inferred in the following situations: (1) colposcopy with confirmation of cervical intraepithelial neoplasia (CIN) and subsequent ablation or excision of severe dysplasia and (2) satisfactory and negative colposcopy without LEEP with at least 1 subsequent negative Papanicolaou test result. A usual care patient with AGUS was determined to have received definitive care if she underwent (1) colposcopy with identification of dysplasia and subsequent removal of dysplasia or (2) unsatisfactory or negative colposcopy followed by LEEP or cold-knife cone biopsy.

Data on follow-up of all abnormal Papanicolaou test results provided at any of the UCI facilities were readily available. For women who elected to receive care at a non-UCI facility, other information was requested at the 12-month follow-up Papanicolaou test and medical records from outside facilities/offices were reviewed. An assessment of the medical records was made to determine if definitive assessment and treatment had been provided within 6 months of the participant’s initial visit to the clinic. For patients with ASCUS and LGSIL lesions in either group, repeat Papanicolaou testing, colposcopy without biopsy, and biopsy/observation of CIN grade 1 lesions were considered definitive treatment.

Statistical analyses included the t test for continuous variables and the χ² and Fisher exact tests to compare categorical characteristics of patients in the single-visit and usual care groups. Two-tailed P<.05 was considered statistically significant. SAS statistical software, version 9 (SAS Institute Inc, Cary, NC), was used.

Oral informed consent was obtained from 4628 eligible white and Latina women (Table 1). Of these, 3526 women were initially randomized; 5 women were later determined to be ineligible when it was discovered that they had no cervix. There were 1716 in the single-visit group and 1805 in the usual care group (Figure). The participants in the 2 study groups were comparable with respect to important demographic characteristics, socioeconomic status, and cervical cancer risk factors. Approximately 80% (2791/3526) of the women randomized in either group of the study were Latina.

Approximately 4% of all Papanicolaou test results in each of the 2 groups were abnormal (single-visit program, 72/1716; usual care, 73/1805), and 1% of results showed high-grade lesions. Fifty-three percent of the women in the usual care group (10/19) received definitive treatment within 6 months for their severe dysplasia compared with 88% of single-visit patients (14/16) (P = .04). Three of 16 women in the single-visit group with severely abnormal Papanicolaou test results did not undergo cervical LEEP in the clinic. One had cervical atrophy and a cold-knife cone biopsy was performed later in the operating room. One patient waited for the results but declined a cervical LEEP and 1 patient left the clinic during the wait; both of these women were lost to follow-up. Severe dysplasia (CIN grade 3) was found in the LEEP specimens of 1 of the 5 patients with AGUS. The pathologic determinations of the remaining HGSIL lesions were 1 invasive cancer, 6 cases with CIN grade 3, and 2 negative specimens.

Although 13 of the 19 women in the usual care group underwent colposcopy within 6 months of their abnormal Papanicolaou test result, only 10 received definitive care. One of the 19 usual care patients initiated evaluation of her abnormal Papanicolaou test result more than 6 months later, and this assessment was not completed. Three of 10 abnormal Papanicolaou test results were AGUS, of which there was 1 case with CIN grade 1, 1 case of CIN grade 3, and 1 case with invasive cancer. The 7 HGSIL specimens comprised 1 CIN grade 1, 2 CIN grade 2, 3 CIN grade 3, and 1 invasive cancer.

There was no difference between the 2 study groups with respect to adherence to evaluation and treatment of the other classes of abnormal Papanicolaou test results. Among women in the usual care group, the degree of severity of the abnormality on the Papanicolaou test did not influence the rate of treatment compliance (Table 2).

Overall, 36% of women in each group presented for a follow-up Papanicolaou test 1 year later (Table 3). Women in the single-visit group with high-grade lesions were significantly more likely to follow up for their Papanicolaou tests 12 months later than women with similar lesions in the usual care group (10 [63%] of 16 compared with 4 [21%] of 19; P = .02). Examination of the other Papanicolaou test classifications did not demonstrate a difference in the follow-up rate 1 year later.

The mean visit time for patients in the single-visit group, defined as the duration from when they came into the clinic until they left, was 2.8 hours. Slightly more than 1 hour (66 minutes) of this time was spent waiting for the transportation, processing, and reading of the Papanicolaou test. In comparison, the mean visit time for the usual care group was 75 minutes. The acceptability of the visit duration, defined as the percentage of women who answered “okay/no problem” to the question, “How was the wait?” (other possible answers included “a little long” and “much too long”), was 76% (1248/1635) in the single-visit group and 89% (1538/1726) in the usual care group (P<.001). Sixty-seven percent (1117/1662) of the usual care patients who completed the questionnaire stated that they would have preferred to wait for their results. Ninety-five percent (1545/1621) of the single-visit patients stated that if possible, they would again request to be in the single-visit program.

We found that the single-visit program was a practical approach to ensuring timely follow-up of severely abnormal Papanicolaou test results in women from a low-income, largely Latino population in Orange County, California. Fourteen of the 16 women with HGSIL or AGUS in the single-visit program received treatment compared with 10 of 19 women with similar abnormalities in the usual care group. Although the number of women at high risk of cervical cancer in this study was small, this program could prevent most cervical cancer if applied to all women with severely abnormal Papanicolaou test results. In this era, when effective treatment of precancerous lesions is available, it is not acceptable for any woman to develop this disease.

The single-visit program was quite acceptable to the women who participated in it and to the pathology department that provided the Papanicolaou test results. However, the majority of the women who inquired about the study were self-referrals who were made aware by our advertising that participation would include the possibility of a wait lasting 2 to 3 hours. For this reason, generalization of the satisfaction results may be limited.

A unique aspect of this program was the ability to immediately process conventional Papanicolaou tests. Immediate assessment of specimens was facilitated by coordinating courier service from the clinical facilities to the UCI pathology department. After an initial period of adjustment, the process was easily incorporated into the laboratory and courier routine. Indeed, the process was similar to that of other pathology specimens that require immediate analysis. Our results suggest that this type of cervical cancer screening program could be incorporated into clinical practices that are in close proximity to a laboratory with minimal inconvenience for the patients or laboratories.

We anticipated that providing women with results of their Papanicolaou tests on the day of the procedure and stressing the importance of follow-up would improve compliance. That was not the case. Only 51% of women with abnormal Papanicolaou test results in the single-visit program and 53% in usual care returned for free screening 1 year later and, overall, only 36% returned. These figures are similar to those previously reported in the literature.^10- 13 The results emphasize the importance of addressing the many barriers to health care access faced by medically underserved populations^4- 8 and the psychological distress that women with abnormal Papanicolaou test results may experience.¹⁶ Additional research is necessary to determine the optimal methods of ensuring follow-up of abnormal Papanicolaou test results in medically underserved populations.

Colposcopy is generally regarded as a necessary procedure in the evaluation of a severely abnormal Papanicolaou test result.¹⁷ In this study, cervical colposcopy and biopsies were not used to confirm the presence of dysplasia and, in essence, the Papanicolaou test was used as a diagnostic test. Dysplasia was identified in only 1 of the single-visit patients with AGUS, and 2 of the patients with HGSIL had no dysplasia. All of the single-visit patients with AGUS underwent endometrial sampling; however, there were no neoplastic changes in any of these specimens. The exclusion of colposcopy among the subset of single-visit patients with severely abnormal Papanicolaou test results precluded the young women of reproductive age in this study who otherwise would have had a satisfactory colposcopy with a CIN grade 1 lesion or no visible lesion from opting for close surveillance with repeated cytology and colposcopy. It is possible that dysplasia may have been present in an area of the cervix that was not removed with the LEEP or in another location of the lower genital tract. Furthermore, the possibility exists that some of the single-visit patients treated with LEEP had CIN lesions that could have been removed with less destruction to the cervix.

Our study was not designed to compare alternative strategies for the initial management of cases classified as ASCUS and LGSIL during screening. The literature indicates that 5% to 17% of ASCUS, 26% to 94% of atypical squamous cells that cannot exclude HSIL, and 15% to 30% of LGSIL found on Papanicolaou tests have associated high-grade dysplasia. In contrast, 9% to 54% of AGUS and 70% to 75% of HGSIL test results are associated with severe dysplasia.¹⁷ The reproducibility of HGSIL is far greater than that of ASCUS and LGSIL, and even the most experienced cytologists are not always able to diagnose ASCUS correctly. Therefore, we did not believe that it was appropriate to perform a cervical LEEP without colposcopy in women with low-grade lesions found on Papanicolaou tests.

Other techniques used to facilitate the immediate identification of dysplasia, such as direct visual inspection with either acetic acid or speculoscopy, are still limited in their effectiveness if the patients do not receive definitive treatment.^18- 19 Now that LEEP without colposcopy has been demonstrated as feasible for women with high-grade cervical cytology, future protocols that are inclusive of atypical squamous cells that cannot exclude HSIL can be considered. Reflex human papilloma virus DNA testing is a lengthy procedure and the specimens are processed in batches. At this time, rapid identification of women with atypical squamous cells who are positive for human papilloma virus DNA is not possible.

In summary, we have demonstrated that a single-visit cervical cancer screening and treatment program is feasible and the degree of acceptability is high. We believe that this strategy is best applied to practices of underserved groups with high rates of loss of follow-up. Single-visit programs provide an opportunity to ensure that severe cervical lesions are treated.