Obstetrics & Gynecology:
A Randomized Trial of the Fischer Cone Biopsy Excisor and Loop Electrosurgical Excision Procedure
Boardman, Lori A. MD, ScM*; Steinhoff, Margaret M. MD†; Shackelton, Rebecca ScM‡; Weitzen, Sherry PhD‡; Crowthers, Laina MD*
From the Departments of *Obstetrics and Gynecology, †Pathology, and ‡the Division of Research, Women and Infants’ Hospital of Rhode Island, Brown Medical School, Providence, Rhode Island.
This study was supported by a grant from the National Institute of Child Health and Human Development (K23 HD01307).
Address reprint requests to: Lori A. Boardman, MD, ScM, Division of Ambulatory Care, Women and Infants’ Hospital, 101 Dudley Street, Providence, RI 02905; e-mail: firstname.lastname@example.org.
Received April 28, 2004. Received in revised form June 21, 2004. Accepted June 24, 2004.
OBJECTIVE: To compare specimens obtained with the Fischer cone biopsy excisor or loop electrosurgical excision procedure (LEEP) with respect to number of specimens obtained, margin interpretability, adequacy of excision, and ease of use.
METHODS: One hundred eligible patients aged 13 years and older were randomly assigned to treatment with the Fischer cone biopsy excisor or LEEP. Eligibility criteria included: (1) cervical intraepithelial neoplasia (CIN) 2 or 3, (2) persistent CIN 1, or (3) cytologic/histologic discrepancy. Following excision, providers ranked ease of use on a scale of 1 to 10. A pathologist blinded to procedure type analyzed specimens for margin interpretability and adequacy of excision. Before study initiation we calculated that a total of 100 patients would be required to demonstrate a significant difference in the interpretable margin rate of 80% for LEEP and 99% for cone biopsy excisor (power 80%, α = .05).
RESULTS: After adjustment for ease of use, lesion size, and degree of neoplasia, the cone biopsy excisor was no more likely to result in a single specimen than LEEP (74% versus 63%, relative risk [RR] 0.93, 95% confidence interval [CI] 0.79 −1.11), to result in a specimen with interpretable margins (65% versus 73%, RR 0.97, 95% CI 0.78–1.22), or to result in a fully excised cervical lesion (72% versus 62% for LEEPs, RR 1.08, 95% CI 0.77–1.52). Providers found their experiences with both Fischer cone biopsy excisor and LEEP cone biopsies to be similar, even after adjustment for year of training and previous experience (RR 0.95, 95% CI 0.72–1.24).
CONCLUSION: The Fischer cone biopsy excisor and LEEP performed similarly with respect to the number of final specimens, margin interpretability, and ease of use.
LEVEL OF EVIDENCE: I
The treatment of cervical intraepithelial neoplasia (CIN) involves the destruction or excision of the abnormal transformation zone. Options for treatment include cold-knife conization, laser conization, cryotherapy, the loop electrosurgical excision procedure (LEEP), and more recently, the Fischer cone biopsy excisor. In the past, cold-knife conization was the standard diagnostic and therapeutic procedure.1 During the past 20 years, a more conservative approach has been developed with the use of electrosurgery.2 Although other therapies may someday supplant the surgical approach, excisional treatment largely constitutes the standard of therapy at present.
In 1989, Prendiville adapted the loop electrosurgical instrument to remove the abnormal cervical transformation zone.2 Loop electrosurgical excision procedure allows for outpatient treatment of CIN and is quick to perform, well tolerated, and less expensive compared with cold-knife and laser conization procedures. Postoperative complications, such as hemorrhage or cervical stenosis, are rare. Furthermore, as compared with cryotherapy or laser vaporization, a tissue sample is provided, and the resulting histopathologic quality of the specimen obtained by LEEP is similar to that of cold-knife conization.3–8 Disadvantages associated with LEEP, however, exist. Because the apparatus provides minimal support, shallow specimens may result. As a consequence, multiple specimens may need to be obtained to complete the excision of the abnormal area. Several studies have shown that this further creates difficulty in interpreting the specimen margins.5,9
The Fischer cone biopsy excisor, introduced in 1994, was designed to minimize the disadvantages of LEEP by increasing the support and stabilization of the excising stainless steel wire.5,8 In 2 randomized trials comparing the LEEP and Fischer cone biopsy excisor, the latter was associated with decreased thermal damage, improved margin interpretability, and an increased likelihood of the excision resulting in a single specimen.8,10 The goal of our study was to compare specimens obtained with the cone biopsy excisor to those with LEEP with respect to the number of cervical specimens obtained, the histologic interpretation of the cone biopsy margin, the adequacy of excision, and ease of performance. In comparison with LEEP, the Fischer cone biopsy excisor specimens were hypothesized to more likely result in a single specimen, to have decreased thermal damage and increased margin interpretability, to more likely result in an adequate excision, and to be easier to use by the provider.
In this randomized clinical trial, patients (aged 13 years and older) seen at the Women and Infants’ outpatient colposcopy clinic at the Women's Primary Care Center were eligible for inclusion and treatment under the following circumstances: (1) presence of CIN 2 or 3 on biopsy, (2) an endocervical curettage with CIN 1 or worse, (3) cytologic/histologic discrepancy, or 4) persistent (2 or more years) CIN 1. Adolescents were enrolled with parental consent. Women who were pregnant, had undiagnosed uterine bleeding, acute infection, or lesions suspicious for invasive carcinoma or glandular disease were excluded. Before beginning the study a sample size calculation was performed. With α set at .05 and assuming a difference in the interpretable margin rate of 80% for LEEP and 99% for cone biopsy excisor, a difference based on prospective trials published to date,4,7,8 a total of 100 women were required to have 80% power β = .20) to detect such a difference. The Institutional Review Board approved the study protocol in July 2002; recruitment began in August 2002 and was completed in November 2003.
Once they were enrolled and consent was provided, patients were randomly assigned to 1 of 2 arms: LEEP or Fischer cone biopsy excisor. Randomization results were generated via a random number table (6-block size) and placed in sealed opaque envelopes. All excisional procedures occurred at the Women's Primary Care Center or the Women and Infants’ operating room. Demographic information was collected before the procedure. Before knowing the instrument to be used, providers applied 5% acetic acid followed by Lugol's solution to the cervix and measured the area of planned excision in 2 dimensions in millimeters. The provider then determined the size of the cone biopsy excisor or LEEP instrument based on lesion size. Providers were specifically asked to indicate whether or not they felt the area to be excised was too large to be removed with 1 pass of the instrument.
Patients taken to the operating room received sedation, and for anesthesia and hemostasis, a combination of 1% xylocaine with 1:100,000 units of epinephrine was injected intracervically. Patients treated in the clinic received 500 mg naproxen and the injection as described above. By using a blend setting, with wattage determined by the size of the excising instrument and manufacturer recommendations, the provider performed a cone biopsy with either the LEEP or Fischer cone biopsy excisor. A foot control was used to activate the current when using both devices. An endocervical curettage was performed immediately after the conization. Adequate hemostasis was achieved with ball cautery and application of Monsel's solution. No patient required further hemostatic management. Before sending the cone to pathology, an incision was made by using cautery at the 12 o'clock position extending to the endocervical canal of all LEEP specimens to mimic the appearance of excisor specimens.
At the conclusion of the procedure, the provider, either a postgraduate third-year or fourth-year resident physician or an attending physician, filled in the data sheet with the number of LEEPs and Fischer cone biopsy excisors done previously and ranked the ease of the procedure on a scale of 1 (easiest) to 10 (most difficult). Of note, attending physicians performed cones only in the event resident physicians were not available. Residents were counseled to evaluate only their experience with the instruments themselves and not with other aspects of the procedure, such as speculum placement or difficulty with visualization of the cervical lesion. A single pathologist, blinded to the type of conization performed, then reviewed all specimens. She assessed the following outcomes: (1) number of specimens obtained, (2) interpretable margin (defined as ≥ 100 microns from neoplasia to thermal artifact), and (3) adequacy of excision (defined as absence of positive margins or endocervical curettage for neoplasia).
Demographic and colposcopic data were evaluated using χ2 or Fisher exact test for categorical data and Student t test for continuous data. For the purposes of the final analysis, we dichotomized our primary outcomes. Procedures resulting in single specimens were compared with those resulting in 2 or more specimens. Interpretable margins were defined as present or not present by the criteria established above. Lesions were considered adequately excised if all surgical margins, endocervical and ectocervical, as well as the postconization curettage, were negative for neoplasia. Ease of use was stratified into 2 categories, easy (1–5) and difficult (6–10). The association between the type of procedure and the primary outcomes was computed by means of relative risks (RRs) with 95% confidence intervals (CIs) by using standard methods.
Of note, the Fischer cone biopsy excisor has been used routinely for the treatment of cervical neoplasia among Women and Infants’ Hospital colposcopy patients. Resident physicians, however, are exposed to LEEP through other physicians in the operating room. Because previous experience may have served as a confounding factor in our study, we required all providers to either have performed at least 5 of each procedure before their participation in this study or to participate in a workshop during which they practiced both procedures on chicken breasts. Further potential confounding factors (such as size and grade of the cervical lesion) were evaluated in the final analysis with multivariable binomial regression methods outlined by Robbins et al.11 This method was used in place of standard multivariable logistic regression. In the case of a “common” outcome, such as occurred in this study, it is not appropriate to use odds ratios as estimates of RRs.12 All analyses were performed by using STATA 8.0 (College Station, TX).
One hundred women were randomly assigned to treatment with either LEEP (n = 51) or Fischer cone biopsy excisor (n = 49). In general, the study population was young, single, and either on government assistance or uninsured. There were no significant differences between the groups with respect to age, race/ethnicity, marital status, mean gravidity or parity, insurance status, mean number of male sexual partners, mean age at first intercourse, smoking, or history of sexually transmitted infections (Table 1). In terms of indication for cone biopsy, the majority of women in both the LEEP and cone biopsy excisor groups had CIN 2 or worse on biopsy and/or endocervical curettage (90% and 86%, respectively). On final pathology from the cone biopsy, 37 (74%) of the women undergoing LEEP and 29 (59%) of the women undergoing treatment with the cone biopsy excisor had CIN 2 or worse (P = .41, full data not presented).
In the unadjusted initial analysis presented in Table 2 the Fischer cone biopsy excisor, compared with LEEP, was more likely, although not significantly, to result in a single pathologic specimen (74% versus 63%, RR 1.17, 95% CI 0.89–1.5). After adjustment for whether the provider felt the lesion too large to be excised in 1 pass and for ease of use, this effect was removed (RR 0.93, 95% CI 0.79–1.1). Interpretable margins were less likely with the Fischer cone biopsy excisor (65% versus 73% with LEEP; RR .90, 95% CI 0.70–1.2); after adjustment for ease of use, this finding did not persist (RR 0.97, 95% CI 0.78–1.2). Among those specimens deemed to be interpretable, cervical lesions were more likely to be adequately excised with the Fischer cone biopsy excisor (72% versus 62% with LEEP; RR 1.16, 95% CI 0.83–1.6). After adjustment for degree of final cervical pathology and for whether the provider felt the lesion too large to excise with a single pass, this result was not significantly altered (OR 1.08, 95% CI 0.77–1.5).
Finally, providers, 90% of whom were resident physicians, reported little difference in the ease of use between the 2 procedures. In the course of the 15 months of patient recruitment, 10 postgraduate third-year residents and 7 postgraduate fourth-year residents participated as providers. Of the 74 procedures done by postgraduate third-year residents, 38 performed LEEP cone biopsies and 36 Fischer cone biopsies. A similar distribution was observed among postgraduate fourth-year residents. Seventy-one percent of the residents felt the LEEP was relatively easy to use, compared with 65% of Fischer users (P = .57). When stratified by year of training (postgraduate third or fourth year) or by previous experience (5–9 procedures performed previously versus 10 or more), providers were equally likely to find the LEEP and Fischer cone biopsy excisor easy to use (adjusted RR 0.95, 95% CI 0.72–1.24). For example, among the 10 postgraduate third-year residents who performed nearly three quarters of the procedures for this study, 71% of those performing LEEPs and 69% of those doing cone biopsy excisors ranked the procedures as relatively easy to perform. The median number of LEEPs and Fischer cone biopsy excisors performed before participation in the trial was 9 and 10, respectively (data not presented).
Cervical conization, either by LEEP or Fischer cone biopsy excisor, is used for both diagnostic and therapeutic purposes in the evaluation and treatment of CIN. How best to manage patients after treatment depends on several factors, including degree of neoplasia and, perhaps most importantly, the status of the surgical margins. Indeed, many authors report a higher risk of persistent or recurrent neoplasia among women with positive margins, an indication of incomplete excision.13–17 Ability to interpret the margins of excision, then, is a critical component in determining the optimal management of patients treated for CIN.
Significant cautery artifact, however, has been problematic in specimens obtained with the loop excision procedure. One of the reported benefits of the Fischer cone biopsy excisor, introduced subsequently to LEEP, was the increased interpretability of the margins of excision. In trials performed both by Fischer,5,8 the inventor of the cone biopsy excisor, and Rosen,10 the histologic margin quality score was better for samples obtained by the excisor than by the loop. While approximately 10–20% of loop specimens were fully uninterpretable (ie, the margins could not be assessed due to thermal damage), less than 2% of specimens obtained by the Fischer cone biopsy excisor were similarly affected. Furthermore, compared with LEEP, the Fischer excisor was associated with significantly higher rates of complete lesion excision8,10 and ease of use.10 Finally, in a retrospective review of specimens obtained with either the Fischer cone biopsy excisor or cold-knife conization, full lesion excision occurred in 94% of excisor specimens and 90% of those obtained with the cold-knife procedure.18
In the present study, we were not able to confirm such findings. Using the data cited previously, we designed a trial with sufficient power to detect approximately a 20% difference in the margin interpretability rate between the two methods. Given the 8% difference we found (in this case, in favor of LEEP), we would have needed more than 1,000 women enrolled in a randomized trial to detect such a difference at a level of acceptable significance. Even if this were accomplished, the clinical relevance of such a slight difference is most likely not appreciable. Nevertheless, the possibility of a type II error remains for our study's findings. We also acknowledge that our results pertain to similar populations of not only the women treated but also the physicians involved. Physicians in training differ from practicing physicians in their level of skill; such a difference may have impacted the outcomes we considered. We doubt this is the case, however, as residents performed the cone biopsies in the reports evaluating the Fischer excisor by Scribner3 and Rosen10 previously cited. Lastly, although Fischer used a tenaculum to stabilize and position the cervix perpendicular to the electrode during the procedure,8 we did not routinely use the tenaculum at the time of conization.
The strengths of the present study include its design as a randomized trial and its requirement that providers perform at minimum 5 previous cones with the devices before participation in the trial. Potential confounders, such as lesion size, ease of use, and degree of neoplasia, were accounted for in the final analysis. Our findings, certainly with respect to LEEP, were well within the range of previous reports. Based on the similarity in our study of the performance of LEEP and the Fischer cone biopsy excisor in terms of margin interpretability, lesion excision and ease of use, either method is acceptable for the treatment of cervical neoplasia.
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© 2004 by The American College of Obstetricians and Gynecologists.