Spies, James B. MD, MPH; Bradley, Linda D. MD; Guido, Richard MD; Maxwell, G. Larry MD; Levine, Betty A. MS; Coyne, Karin PhD, MPH
Uterine leiomyomas are the most common benign tumors of the female reproductive tract. They cause a variety of symptoms including menorrhagia, dyspareunia, bloating, pelvic pressure, urinary urgency, and frequency of urination and are among the most common reasons for gynecologic intervention. The prevalence increases as a woman progresses through her reproductive years, and the symptoms associated with leiomyomas most commonly occur in a woman's 40s, with African Americans more likely to be diagnosed at a younger age.1
Symptoms that negatively affect a woman's daily life are a primary indication for treatment. Hysterectomy, myomectomy, and other operative interventions are commonly required at a significant cost to the health system, and medical management and office visits add to that burden.2 Leiomyomas are the most common reason for hysterectomy in this country.3
Hysterectomy has been the definitive treatment of leiomyomas, but myomectomy is also a common option for women seeking to become pregnant, and there are a variety of minimally invasive variations of both these procedures. Newer options, such as uterine artery embolization and magnetic resonance–guided focused ultrasonography, are nonsurgical treatments also targeted at leiomyomas. During uterine artery embolization, the vascular supply to the leiomyomas is occluded, resulting in ischemic infarction of the leiomyomas, whereas magnetic resonance–guided focused ultrasonography uses high-intensity focused ultrasonography transcutaneously to thermally ablate leiomyomas. Although there have been comparative studies among these treatments, a limiting factor in investigating uterine leiomyoma therapies has been the lack of validated outcome measures.
Leiomyoma symptoms experienced by patients are subjective and have not been shown to correlate with leiomyoma number, size, location, or any other clinical measure of leiomyomas. As symptoms and their impact on quality of life and activities of daily living are the primary indication for therapy and presumably their resolution is one measure of success, a validated questionnaire to measure this impact is needed. Such an instrument, the Uterine Fibroid Symptom and Quality of Life questionnaire (UFS-QOL), has been created and validated4 and is intended to assess leiomyoma-related symptoms and health-related quality of life impact of those symptoms. The initial validation of the questionnaire was cross-sectional and not longitudinal; it was not validated in hysterectomy patients, and its validation in normal participants was based on a limited number of women.
To address these issues, we undertook this study to validate the UFS-QOL questionnaire in a normal population and to validate the questionnaire in a posthysterectomy patient population. Additional goals included evaluating the longitudinal change in symptoms and health-related quality of life in patients undergoing hysterectomy, myomectomy, and uterine embolization and comparing the outcomes of each intervention with the normal control group and the other therapies. This article will report the findings of these latter goals and validation results will be presented in separate publications.
MATERIALS AND METHODS
This was a multicenter comparative, prospective outcome study of patients undergoing treatment for uterine leiomyomas and a normal control group. Three university medical centers and one academic military medical center recruited patients undergoing leiomyoma treatments. Normal control group members were recruited at three of these centers along with two private practices in the Washington, DC, metropolitan area. All of the participating center's institutional review boards approved the study. The study was conducted in compliance with the Health Insurance Portability and Accountability Act (HIPAA) and the principles outlined in the Declaration of Helsinki. Each participant provided written informed consent before study participation.
Each participant in the leiomyoma treatment group had a routine history and physical examination, supplemented with imaging as appropriate, to confirm her diagnosis. Women in the normal control group were recruited as they completed a routine well-woman evaluation by their gynecologist. The initial inclusion criteria for all groups were premenopausal women aged 35 years and older and aged 50 years and younger who were willing to provide written informed consent and able to speak and read English. Additionally, for the leiomyoma treatment group, the women had to be scheduled to undergo hysterectomy, myomectomy, or uterine embolization for treatment of uterine leiomyomas. The women in the normal control group had to have no history of uterine leiomyomas, no current gynecologic problems, and a normal gynecologic examination with a regular menstrual cycle (one period per month) at the time of enrollment. After the study began, the age inclusion range was expanded to those 30 years and older and those 50 years old and younger due to slow enrollment among normal controls and myomectomy patients. Exclusion criteria for both groups were current pregnancy, cognitive or psychiatric impairment that would interfere with completing the questionnaires, and comorbidity with life expectancy to be less than 1 year or if the woman was an active duty military member (Walter Reed enrollees). Active duty military members were excluded from the study as they are not allowed to be paid for participation in medical research and are subject to deployment, which could have made follow-up difficult.
The baseline questionnaire packet contained a baseline demographic and clinical history questionnaire, the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire,4 and the Medical Outcomes Study Short Form 36 (SF-36) questionnaire.5 Participants were provided the questionnaire packet at the time of recruitment and asked to complete the questionnaire packet within 1 week before their scheduled treatment. The participant mailed the completed questionnaire packet in a preaddressed stamped envelope to the data center. For the women in the normal control group, the baseline questionnaire packet was completed at the time of enrollment and returned to the study coordinator at the site or mailed from home once completed.
For participants in the leiomyoma treatment group, the treating physician completed a clinical data form noting the extent of leiomyoma disease based on the ultrasound or magnetic resonance imaging (MRI) report, as well as his or her clinical assessment of uterine size by physical examination, operative details, and periprocedural complications (those occurring within 30 days of treatment), using standardized definitions of adverse event severity.
Follow-up questionnaire packets were mailed to each participant at 6 and 12 months. The initial study design was to include a 5-year follow-up period; however, due to funding limitations, the study was terminated after 1 year of follow-up. The following forms were used for each follow-up interval: the Follow-up Questionnaire, UFS-QOL (or UFS-QOL-Hysterectomy), and SF-36. Participants mailed the completed questionnaires in a preaddressed stamped envelope to the data center. To encourage participation at each follow-up, participants were mailed $20 upon receipt of each questionnaire packet. For both study groups, participant discontinuation or withdrawal and the corresponding reason were recorded.
The UFS-QOL consists of an eight-item Symptom Severity scale and 29 health-related quality-of-life questions, which include six subscales: Concern, Activities, Energy/Mood, Control, Self-Consciousness, and Sexual Function.4 The Symptom Severity subscale and the health-related quality-of-life subscale scores are inverse, with higher symptom scores indicating greater symptom severity while higher health-related quality-of-life subscale scores indicate better health-related quality of life. Subscale scores are transformed to a 0-to-100 scale.
Because the wording of the UFS-QOL is based on the presence of uterine leiomyomas, this questionnaire was modified to allow women with hysterectomies to respond. The UFS-QOL-Hysterectomy retains the same questions as the UFS-QOL but differs in the introductory paragraph where participants are asked to consider each symptom as it relates to how they feel now after their “hysterectomy” as opposed to “uterine fibroids or menstrual cycle.”
The SF-36 is a 36-item generic health status measure that is composed of eight subscales: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health as well as two summary scores, the physical component score and the mental component score, each of which is based on specific subscales.5 Individual items from each subscale are combined to form a subscale rating and transformed to a 0-to-100 scale. The physical component score and mental component score are calibrated so that their mean score or norm is 50. For both the subscales and the summary scores, higher scores indicate better quality of life and the recall period is 4 weeks.
The sample size for this study is based on the within-individual change over time. For the purposes of this study, success was defined as a minimum improvement of 20% in the UFS-QOL Symptom Severity subscale score from baseline to final analysis. Thus, if uterine artery embolization and myomectomy patients have a mean Symptom Severity score of 44.0 (based on the initial validation sample) with a standard deviation of 24.0, a 20% change from baseline would yield a score of 35.2. With an alpha of 0.05 and power of 0.80, a sample of 61 patients per group would be needed to detect a change of 20% within each group. To compensate for a projected 15% patient dropout rate per year, an additional 10 patients were added for each planned year of follow-up yielding an initial recruitment rate of 100 patients per group (based on the original plan of 5-year follow-up).
The analyses were conducted using a per-protocol patient population. No data imputations were performed for missing data. Scoring of the questionnaires was performed according to the developers' guidelines. All statistical tests were identified a priori.
Descriptive statistics were used to examine patient sociodemographic and clinical characteristics and procedural information. Questionnaire scores were similarly summarized at each time interval. General linear models were used for fibroid treatment group comparisons at the same time periods with pair-wise comparisons between means performed using the Scheffé test adjusting for multiple comparisons. All statistical tests were two-tailed and were conducted with type I error probability fixed at 0.05. All analyses were performed using SAS 9.1.3 (SAS Institute).
Participants were recruited between October 2006 and March 2008; patient recruitment and follow-up are summarized in Figure 1. A total of 459 patients were enrolled: 130 normal participants and 329 leiomyoma patients. Women with major protocol violations were excluded from the analyses. The reasons for exclusion were as follows: participants younger than 35 years of age (n=3, excluded before the eligibility criteria were expanded), normal control group members who self-reported leiomyomas (n=3), normal control group member with previous hysterectomy (n=1), normal control group member without a regular menstrual cycle (n=1), and uterine leiomyoma patient reporting no uterine leiomyomas (n=1). Of the remaining participants, 101 normal participants and 274 leiomyoma patients returned a completed baseline questionnaire and qualified for the study representing the per-protocol study sample. There were 107 embolization, 61 myomectomy, and 106 hysterectomy patients. Enrollment goals were met in each of the groups except the myomectomy patients, with lower than anticipated enrollment. The numbers of patients completing each follow-up visit are provided with final completion rates of 88.1% for normal participants, 83.2% of embolization, 90.2% of myomectomy, and 85.8% of hysterectomy patients.
The baseline characteristics of the groups are compared in Table 1. Although there were differences in the distribution of enrollees by site, there were no differences in the outcomes based on site. Differences were present in the age of participants, as normal controls were slightly younger than the leiomyoma treatment group as a whole (40.8 compared with 43.1, P<.001) and myomectomy patients were younger than either the uterine artery embolization group or the hysterectomy group (40.6 compared with 43.2 compared with 44.5 respectively, P<.001). Normal control group members were less likely to have comorbid conditions, most notably hypertension (1.2% compared with 6.9%, P=.012). Normal control group members were less likely to have irregular menstrual bleeding, particularly when compared with the uterine artery embolization and hysterectomy groups. Although there was no difference in the frequency of previous pregnancy between the controls and leiomyoma group as a whole, the myomectomy patients were less likely to have had previous pregnancy.
Table 2 presents the anatomic details of the leiomyoma treatment groups before treatment. The estimated uterine sizes by physical examination were not different between the groups, with the means of 13–14 weeks' size. The uterine volumes as measured on imaging were less for myomectomy. The number of leiomyomas and the mean diameter of the largest leiomyoma in each patient were not different between groups. Myomectomy patients were more likely to have submucosal leiomyomas, with 48% having either partial or completely submucosal leiomyomas. This is also reflected in the distribution of surgical approaches for myomectomy (Table 3), with 44% of myomectomies using the hysteroscopic approach, while 50.9% had an abdominal operation. Abdominal hysterectomy was the most common approach for that procedure (43.8%), followed by laparoscopic hysterectomy (32.4%). The standard approach to uterine embolization was bilateral embolization of the uterine vessels, which was completed in 95% of cases. In some patients, the ovarian artery replaces the uterine artery or supplements uterine leiomyoma supply, which accounts for the ovarian artery embolization procedures that were done in two patients. The length of stay was shorter for uterine embolization compared with the other therapies (mean 1 day uterine artery embolization, 2.1 days myomectomy, 1.9 days hysterectomy, P<.001), despite 42% of patients undergoing myomectomy as an outpatient procedure. Uterine embolization was done with a standard 1-night stay in the hospital, with only five in which the procedure was performed as a same-day procedure.
The frequency of adverse events was similar among the groups (6.7% of uterine artery embolization, 13.3% of myomectomy, and 13.3% of hysterectomy, P=.58; Table 3). None of the adverse event outcomes were different among the groups, and there were no deaths or permanent injuries secondary to adverse events.
In the left half of Table 4, the baseline UFS-QOL and SF-36 scores of normal participants and the combined leiomyoma treatment group are presented with highly significant differences between the groups in all subscales, demonstrating the negative impact of leiomyoma symptoms on health-related quality of life. When comparing the baseline status of leiomyoma patients by treatment group, no differences were found among the groups, except the mental health score of the SF-36 where the hysterectomy group reported significantly lower mental health than the uterine artery embolization group.
Table 5 presents the scores from both the UFS-QOL and the SF-36 at 12 months, demonstrating marked improvement in the leiomyoma group scores as a whole and also in each of the treatment groups. The mean scores of the normal controls generally remain better when compared with the leiomyoma treatment group as a whole. The degree of improvement is greatest among the hysterectomy patients, with some subscale scores exceeding those of the normal group. Similar scores were noted at 6 months (not shown).
The absolute values of the change scores for each group are shown in Figure 2. Among the women in the normal control group, there were no significant changes in scores from baseline to 6 and 12 months. In contrast, there was a dramatic reduction in Symptom Severity scores and increase in all UFS-QOL health-related quality-of-life subscales in all treatment groups, with the scores approaching the mean for normal controls. Across the leiomyoma treatments, the greatest improvement was noted in the Symptom Severity scores and the least with the Sexual Function subscale. The posttreatment scores were most dramatically changed in the hysterectomy group, and comparison of scores between normal participants and hysterectomy patients at 6 and 12 months were very similar, with fewer symptoms in the hysterectomy group and better or similar scores than normal controls in most dimensions (Table 6).
Assessing the outcome from the treatment of leiomyomas has been a major challenge for researchers. There are no reliable objective measures of outcome that have been demonstrated to correlate with symptom control. Whereas the extent of menorrhagia can be estimated by measuring hemoglobin, assessing the volume of blood directly using the alkaline hematin method,6 using a pictorial blood loss assessment chart7 or a blood loss questionnaire,8 none of these methods measures the sum of leiomyoma symptoms, including pain, pressure, and urinary symptoms. Some methods, such as directly measuring menstrual blood loss or use of the pictorial blood loss assessment chart, are also cumbersome and may hinder patient recruitment in research studies. In addition, none of the blood loss methods assess the effects of leiomyoma symptoms on health-related quality of life. Efforts to include quality-of-life measures in leiomyoma clinical research studies have been inconsistent. A review in 2006 of studies of health-related quality assessment in women undergoing treatment for a range of gynecologic conditions, including leiomyomas, concluded that there was no uniformity of assessment of outcomes for uterine leiomyomas, and this lack of uniformity limits the comparison of various studies.9 The goal of developing the UFS-QOL was to provide a simple means to determine the severity of leiomyoma-related symptoms, to measure the related impact on health-related quality of life, and to assess the change that occurs as a result of therapy.
This study presents the comparative outcomes from patients undergoing leiomyoma therapies using the UFS-QOL. These data suggest an advantage for hysterectomy over both myomectomy and uterine embolization. Symptom scores are much better for hysterectomy patients, exceeding even those of normal patients, although this is likely related to the symptom score being heavily influenced by menstrual bleeding, absent in women after hysterectomy. Having said that, there is also a clear advantage in the health-related quality-of-life score for hysterectomy when compared with myomectomy and uterine embolization, which reflects broader measures of health status. There was no difference between the scores for myomectomy and embolization, with mean scores for both procedures approaching normals and markedly improved over baseline. On other measures, embolization had an advantage. Length of hospital stay was shortest for embolization at 1 night and longest for myomectomy at 2.1 days, despite nearly half of the myomectomies being performed as outpatient procedures. There were no differences in minor or major adverse event rates, confirming the relative safety of all three therapies.
In recent years, there have been several randomized studies published comparing various leiomyoma therapies with hysterectomy using standard quality-of-life questionnaires, commonly either the summary scores or subscales of the SF-36. For this reason, we used that questionnaire as our reference standard. In our study, we found that there were very significant differences between baseline SF-36 scores and scores after treatment for the fibroid treatment group. On the other hand, the SF-36 subscales and summary scores in our study did not reveal any difference among the three leiomyoma treatments at 12 months after treatment, suggesting equivalent outcomes. This is similar to what has been found in other studies. In 2004, Kuppermann et al10 compared hysterectomy to medical therapy using the mental and physical summary scores from the SF-36 as key outcomes and found no differences between them at 24 months after treatment. Another study compared hysterectomy to levonorgestrel-releasing intrauterine device with the SF-36 and EuroQol 5D as the key outcome measures.11 Although significant improvement was found after treatment for both groups, no difference was reported between the two treatment groups based on these two questionnaires. The Embolisation versus Hysterectomy Trial from the Netherlands compared the outcomes of hysterectomy with uterine artery embolization, also using the EuroQoL 5D and the SF-36 among other measures.12 Again, both groups noted substantial improvements in quality of life, but no differences in the mental and physical component scores of the SF-36 were evident between the groups at 2 years after treatment. Finally, the Randomized Trial of Embolization Versus Surgical Treatment for Fibroids from the United Kingdom compared uterine artery embolization with best surgical alternative (myomectomy or hysterectomy)13 using the same measures and also found no differences in the final quality-of-life scores between surgery and embolization.
This equivalence might suggest uniform outcomes from all these interventions, but also might reflect a lack of sufficient responsiveness in the questionnaire, that is, its ability to detect small differences in symptom and quality-of-life status between treatments. In our study, the magnitude of the change in subscale scores with the UFS-QOL was much greater than those noted in the SF-36, which we believe reflects the sensitivity of using a disease-specific questionnaire. For the leiomyoma treatment group as a whole, mean Symptom Severity score decreased by more than 40 points and the health-related quality-of-life total score increased by a similar magnitude at 12 months, suggesting that the questionnaire is very responsive to change in status. During the same interval, the normal control group members had no appreciable change in scores, underscoring the stability of the questionnaire responses in women without gynecologic conditions. In contrast to our findings using the general quality-of-life measures, we found that many of the subscales and both summary scores of the UFS-QOL did detect a difference between hysterectomy and the other two leiomyoma therapies, with better outcomes for hysterectomy. This suggests that the UFS-QOL can detect smaller but still meaningful differences in status in patients with symptomatic leiomyomas than might be detected by general quality-of-life questionnaires.
In addition to confirming the discriminatory ability of the UFS-QOL, this study advances our understanding of questionnaire responses in two important groups: normal women in the same age range as leiomyoma patients and women who undergo hysterectomy. Without data from these benchmark groups, it is difficult to assess the relative effectiveness of any other leiomyoma therapies.
The scores on the normal cohort in this study were remarkably stable at the 6- and 12-month follow-up intervals. This provides a normal range of scores for comparison with those from women with leiomyomas. The mean Symptom Severity score for normal participants at baseline was 15.8 and the health-related quality-of-life total score was 92.8. These vary somewhat from the original validation,4 which reported mean normal scores of 22.5 and 86.4, respectively. The currently reported scores are likely to be more reliable as these normal control participants were screened to ensure the absence of leiomyomas, they were in the same age range as those with leiomyomas, the estimate was made three times over the course of a year, and the study sample size was more than three times larger.
As a basis for comparison, this study demonstrates that this group of hysterectomy patients had an excellent outcome, with scores on both the UFS-QOL and the SF-36 that were at or near the mean scores of normal controls of the same age. It also demonstrated that both myomectomy and uterine embolization provide very substantial symptom relief and improvement in health-related quality of life as well. A number of earlier studies evaluating newer therapies, such as magnetic resonance–guided focused ultrasound therapy,14 mifepristone,15 as well as a large cohort treated with uterine embolization16,17 have used the UFS-QOL and the outcome scores from those therapies may now be evaluated in the context of those reported in this study.
There are limitations in this study. First, the leiomyoma group was not randomly assigned, and our analysis did demonstrate some differences between the treatment groups. There were also differences in the number of enrollees among the leiomyoma therapies and normal participants among the different sites, although we did not find substantive differences in baseline characteristics or outcome by site. The treatments were self-selected by the patients, and the patient self-choice could affect patient perception of outcome. Similarly, the assessment of the extent of leiomyomas was recorded by the treating physician and not a blinded research assistant, and this could potentially bias that assessment. We also did not meet our recruiting goal for myomectomy, and it is possible that the smaller sample size in this group may have masked differences between it and uterine embolization. This smaller sample size was counterbalanced to some degree by the decrease in the intended duration of the study, which had the effect of diminishing the number of participants needed to detect differences between the groups. There also was some loss to follow-up in all the groups, with 10–15% of patients not completing the study, depending on the treatment group. Finally, the length of follow-up is only 12 months and therefore we cannot make statements regarding the long-term outcomes from the leiomyoma therapies.
Despite these limitations, this study demonstrates that these three leiomyoma therapies are effective, with hysterectomy demonstrating the greatest improvement. The study also establishes the UFS-QOL as a useful tool for assessing leiomyoma therapies and provides new benchmarks for comparison of therapeutic outcomes.
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