This article is based on a presentation at the conference on Women's Health and the Environment: The Next Century--Advances in Uterine Leiomyoma Research held 7-8 October 1999 in Research Triangle Park, North Carolina, USA.
Address correspondence to D.L. Olive, 162 Hearst Ave., San Francisco, CA 94131 USA. Telephone: (415) 239-1363. E-mail: lapskyboy@aol.com
Received 23 February 2000; accepted 16 May 2000.
Leiomyomata of the uterus (fibroids) are among the most common tumors of women, yet the information gathered to guide our treatment has been rudimentary. Evidence-based medical principles suggest two levels of understanding are required to provide optimal therapy: a firm idea of the pathophysiology of the disorder, and treatment trials to validate the theoretical interventions derived from the knowledge of the pathophysiologic process. The pathophysiology of fibroids is not totally understood, but several facts are evident. It is now clear that the tumors are monoclonal, as different genetic aberrancies may arise in two fibroids derived from the same uterus (
1). In addition, leiomyomata are sex-steroid hormone dependent, as estrogen and progesterone are both believed to stimulate fibroid growth (
2,3).
With this understanding of the process of fibroid initiation and growth, both medical and surgical therapies have been designed. This review discusses the various treatment alternatives, as well as the evidence supporting their role in the armamentarium to combat these tumors.
As treatment options are evaluated for leiomyomata, several problems are apparent. First, the term leiomyoma actually encompasses a heterogeneous group of tumors with various characteristics and resulting symptoms. For instance, a tumor may be small and submucosal, producing abnormal uterine bleeding; a second might be 15 cm subserosal and causing constipation. The optimal treatments for these tumors are likely to be quite different, and if these variables are not appropriately stratified in a study, the resulting data are meaningless.
Second, there are few comparative studies assessing multiple therapies, and of these only a handful are randomized clinical trials. Thus, the quality of data available for recommendations is rarely optimal (4). Most comparative studies are, in fact, historically controlled, introducing a wide variety of biases that render the conclusions of dubious value (5).
A third issue in these studies is the outcome variable; rarely is quality of life or even the effect upon presenting symptom evaluated. Instead, a variety of surrogate outcomes have been employed, such as blood loss, length of surgery, and rate of adhesion formation, each of limited applicability to the real issues involved (6).
Finally, these studies are often surgical trials, and as such face the problem of efficacy versus effectiveness. That is, how a surgical technique is performed by an expert under ideal circumstances may differ radically from how the average physician performs the procedure under standard conditions (7). Thus, the generalizabilty of these data may be open to question.
These and other caveats lurk in the background as we evaluate these treatment options. Nevertheless, evidence-based medicine mandates that medical decision making must proceed with the best available evidence. That evidence is presented below.
Hysterectomy
Hysterectomy is the "gold standard" for treatment of fibroids, in that with removal of the uterus the elimination of presenting symptoms should be extremely high and the recurrence risk virtually zero. Indeed, satisfaction rates following hysterectomy exceed 90% (8). However, the procedure is not without problems. First and foremost, reproductive potential is eliminated unless surrogate in vitro fertilization is desired. In addition, the procedure has a high rate of minor complications and, occasionally, major morbidity (9). Finally, occasionally ill patients may be poor candidates for such an invasive major surgical procedure.
Hysterectomies may be performed by a variety of techniques: abdominal, vaginal, laparoscopic, and laparoscopically assisted (LAVH). Clearly, specific circumstances of size and location of myomas may dictate a particular approach. However, randomized clinical trials have been performed to help delineate which surgical approach is optimal under standard circumstances. The LAVH is at the center of these trials, as its role in the treatment of enlarged uteri has been repeatedly questioned. When comparing the LAVH to vaginal hysterectomy, no apparent advantage was seen with the laparoscopic approach (10). However, the LAVH is advantageous, when compared to the abdominal hysterectomy, for uteri 12-18 weeks in size (11). No other high-quality comparative trials have been conducted among these routes of entry.
Another issue is the degree to which hysterectomy need be performed. Recently, the total hysterectomy has been challenged by the supracervical hysterectomy, performed either at laparoscopy or at laparotomy. A number of theoretical advantages have been espoused regarding the supracervical hysterectomy (Table 1). However, to date few data exist to accept or refute these hypotheses (12). Those studies addressing the issues are generally small and of poor quality, and most are uncontrolled or historically controlled. The exception is the effect of supracervical versus complete hysterectomy on urinary function, where two prospective trials (one randomized) have failed to demonstrate a difference (13,14). However, sample size is small in each case. Similarly, many physicians have championed the complete hysterectomy due to perceived disadvantages of the supracervical approach (Table 1). Although such arguments are logical, data are again lacking (12). Thus, no firm conclusions can yet be drawn regarding the preferred type of hysterectomy for fibroids, and decision making should be left to the individual and her practitioner.
Abdominal Myomectomy
When conserving the uterus is desired in the treatment of uterine fibroids, the most commonly used procedure is the abdominal myomectomy. The concept is straightforward: the abdomen is entered, the uterus is isolated, the fundus is incised, the myomas excised, and the uterus and abdominal wall are surgically repaired. However, the uterus (with myomas) may have considerable bulk, impressive blood supply, and a highly adhesiogenic tendency when damaged. Thus, technique for performing abdominal myomectomy may be key to the results obtained.
Pretreatment of the uterus with a gonadotropin-releasing hormone (GnRH) agonist has been evaluated in several randomized trials and one meta-analysis (15). Pre- and postoperative blood counts are significantly improved by this medical therapy, and both uterine and fibroid volumes are reduced. Blood loss at surgery and the rate of vertical incisions were also reduced. Although a trend exists toward an increased risk of recurrence of myomas after GnRH analog use, the results to date are equivocal due to the limited sample size (15). Thus, there do seem to be distinct advantages to the use of GnRH agonists as pretreatment prior to surgery; however, potential disadvantages such as recurrence rate and cost have not been adequately assessed.
Another issue with myomectomy is hemostasis. For this purpose, three techniques have been advocated: a) vasopressin solution injected into the uterus, b) tourniquet compression of the uterine vasculature, or c) use of rubbershod clamps on the uterine and infundibulopelvic vessels. In a randomized, placebo-controlled trial, the use of vasopressin for abdominal myomectomy significantly reduced operative blood loss (16) and has proven statistically (although not clinically) superior to the tourniquet (17).
Adhesion formation is a significant issue with myomectomy in that the vast majority of such patients wish to preserve fertility potential. Technique plays an important role in adhesiogenesis, as a posterior incision is much more likely to result in adnexal adhesions than one performed anteriorly (18). Adhesion prevention barriers have been tested, and all currently available adhesion prevention adjuvants have been demonstrated in randomized trials to reduce adhesion formation following myomectomy (19-21).
Data regarding recurrence following myomectomy are sparse and generally of poor quality. The largest available study is that of Candiani et al. (22), who reviewed 622 patients who underwent myomectomy over a 14-year period. They judged recurrence by ultrasound if the patient was noted to have an abnormal examination or symptoms of recurrence. All patients were seen at least once a year. The cumulative 10-year recurrence rate was 27%, increasing with length of follow-up. There were no differences observed in recurrence rates by age at diagnosis or site of the myomas, although patients with more than one myoma tended to recur more frequently.
Myomectomy has long been considered a risk factor for obstetric-related uterine rupture. It has been hypothesized that if the uterine cavity is entered at the time of surgery, the risk of rupture is increased. One study confirms this theory (23), but no such association was noted in two others (24,25).
Laparoscopic Myomectomy
An alternative to myomectomy at laparotomy is the performance of the procedure via laparoscopy. Several issues must be addressed when comparing the laparoscopic approach to that of open surgery: time, blood loss, complications, cost, adhesion formation, and future fertility. Of these, only adhesion formation has been evaluated with a prospective trial. In one study, no difference in adhesion formation was seen between the two techniques (26). However, in this investigation, the same size suture (3-0) was used for both surgeries, a situation not likely to be generalizable to the vast majority of gynecologic surgeons. Poor-quality data suggest laparoscopic myomectomy is more time consuming, but recent advances in instrumentation may narrow this time gap. The only apparent limitation now recognized with the laparoscopic approach is fibroid number; when more than four fibroids are present, most surgeons prefer an open surgical approach.
Hysteroscopic Myomectomy
A hysteroscopic approach to fibroid resection is feasible when the tumor protrudes into the uterine cavity (submucous myoma). In this instance, the use of an operative hysteroscope to resect the fibroid is quick and easy. Pretreatment with GnRH agonist is indicated if the largest diameter of the fibroid is within the endometrial cavity, although no data exist to verify the value of this approach.
Several dangers of hysteroscopic excision have been noted, principally due to the use of hypotonic, hyponatremic fluid distension media for the uterus (27). The use of an automated fluid management system is essential to prevent excessive absorption of this fluid under such circumstances (28). Currently, resectoscopic devices are being developed that can be used in physiologic solutions (29).
The risk of recurrence of myomas following hysteroscopic resection appears to be higher than that for the abdominal approach, although no direct comparisons exist. Using survival analysis, Hart and colleagues (30) show the risk of further surgery following the procedure is 21% at 4 years. By contrast, Vercellini and colleagues (31) had a 3-year cumulative recurrence risk of 34%. This latter investigation also reported the reproductive success in infertile women undergoing the procedure: the 3-year conception rate was 33-49%, depending upon the type of lesion.
Myolysis
The theory behind myolysis is that by destroying either fibroid tissue or its blood supply the resulting shrinkage of the tumor will be sufficient to significantly diminish symptoms. To this end, a laparoscopic approach using the Nd:YAG laser, bipolar needles, monopolar cautery, and cryotherapy have been demonstrated effective (32-34). However, the length of follow-up is limited, and the long-term recurrence risk is unknown. Nevertheless, the ability to reduce to fibroid from 40 to 80% with a simple, brief, laparoscopic procedure is enticing, and further study is clearly needed.
Uterine Artery Embolization
A new technique for the treatment of fibroids is the use of uterine artery embolization. This approach has long been available as a means of stopping hemorrhage, but only recently has it been applied in an attempt to shrink fibroids. The procedure involves catheterization of the uterine arteries via femoral artery access. Once in place, polyvinyl alcohol particles are injected into the arteries to occlude them. Data suggest that in experienced hands this procedure is a technical success in more than 95% of women (35,36). Uterine volume appears to decrease 40-50%, and symptomatic control is achieved in approximately 80%. Goodwin et al. (35) reported that 81% of women still had uteri at 16 months' follow-up; Hutchins reported only 3.7% needing additional surgery, although follow-up was brief.
Complications of the procedure should be a concern. More than 40% of patients suffer a temporary temperature elevation; extreme pain is noted anecdotally in up to 20%. One death has been reported (37); few studies contain sufficient details of complications to allow an accurate assessment of risk. However, the thousands of unpublished cases to date make this procedure a popular and widespread alternative to traditional surgical therapy.
Medical Therapy
In those patients wishing to avoid surgical treatment of symptomatic fibroids, the use of long-term medical therapy is an alternative. This medical treatment approach can be achieved by combining GnRH agonist with low-dose sex-steroid hormone therapy, the so-called add-back regimen. This treatment approach allows for suppression of endogenous ovarian sex-steroid production, creating a hypoestrogenic/hypoprogestrogenic state, which causes uterine and fibroid reduction. Adding back a small amount of hormonal therapy allows minimization of side effects, while hopefully not impacting upon treatment efficacy.
Several pilot studies have investigated this approach, each utilizing only a handful of patients (38,39). Their data demonstrate that fibroid volume can be decreased satisfactorily with GnRH-agonist therapy, and regrowth will not occur with the addition of low-dose sex-steroid replacement (conjugated equine estrogens 0.625 mg/day and medroxyprogesterone acetate 10 mg 10 days/month). However, higher-dose medroxyprogesterone alone will apparently cause regrowth (38). Unfortunately, follow-up is limited to 1 year; long-term results with this approach of low-dose hormone replacement are unknown at this time.
A number of therapies are currently available for the treatment of uterine leiomyomata, each with advantages and disadvantages. This array of approaches enables the modern clinician to present the patient with symptomatic fibroids with a variety of options; the patient now has been empowered to help select a treatment modality that best fits her desires for degree of surgery, risk of recurrence, and need for future fertility. Nevertheless, most alternatives to the traditional hysterectomy are new and poorly studied. Little is known regarding risks, costs, and comparative value. Furthermore, many such procedures are still in a state of evolution, with study results having little applicability to the modern performance of such procedures.
Although it is true that sparse data exist to support even the traditional techniques, the newer approaches are primarily unstudied, with little true investigation to support their use. High-quality research is sorely needed. Randomized trials should be performed. Attention to appropriate methods of inclusion, patient evaluation, outcome measures, and analysis of the data must increase. Finally, true cost analysis methodology should be applied to these questions.
The treatment of uterine fibroids is far from an exact science at this time. It is incumbent upon us as clinicians and scientists to demand better information before we embark upon unproven therapeutic courses.
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Last Updated: October 3, 2000
