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Hartmann KE, Fonnesbeck C, Surawicz T, et al. Management of Uterine Fibroids [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2017 Dec. (Comparative Effectiveness Review, No. 195.)
Condition
Uterine fibroids (i.e., leiomyomata) are common benign smooth muscle tumors of the uterus. The etiology is not well understood, and a variety of factors including race/ethnicity, parity, and age at menarche have been examined. By age 49, more than 70 percent of white women and 84 percent of African American women have fibroids documented by imaging or surgical records.1 In the United States, an estimated 26 million women between the ages of 15 and 50 have uterine fibroids.1-3,1-3,5,6,27,28 Fibroids may be asymptomatic, or can produce health effects that include profound bleeding and anemia, pelvic pressure or pain, urinary frequency, abnormal bowel function, pain with intercourse, as well as effects on fertility and pregnancy outcomes.29 More than 15 million US women will experience associated symptoms or health concerns.5,6 A disproportionate number of black women have symptoms in part due to earlier age at onset of fibroids with larger and more numerous tumors.1-3,27,28,29 Black women are also more likely to have surgical interventions for fibroids.7
Symptoms from fibroids can result in considerable personal and societal costs including diminished quality of life, disruption of usual activities and roles, lost work time, and substantial healthcare expenditures. Across types of interventions, direct annual healthcare costs in the United States are projected to exceed $9.1 billion. Lost wages, productivity, and short-term disability are estimated to total another $5 to $17 billion annually, with roughly $4,624 in costs per woman in the first year of diagnosis.8,9
Management of Uterine Fibroids
Asymptomatic fibroids do not require intervention. Discussion of management options for symptomatic fibroids is among the most frequent conversations in gynecology and primary care and is the most common reason for gynecologic surgery.30,31 These discussions are shaped by future reproductive goals.32,33 Treatment options differ in fundamental aspects such as cost, invasiveness, recovery time, risks, likelihood of long-term resolution of symptoms, need for future care for fibroids, and influence on future childbearing. Thus synthesis of available evidence is crucial to assist women and their care providers in making well-informed and personalized decisions.
This report is organized from least invasive to more invasive treatment options: expectant management, then medical treatment, and then outpatient procedures and major surgeries.
Medications
In any given year, a greater proportion of women with symptomatic fibroids receive medical therapy than surgery.9 Though no medications have been specifically cleared by the U.S. Food and Drug Administration (FDA) for fibroid treatment, several medications are used off-label for fibroid symptoms. Those commonly used in clinical practice include birth control pills, stool softeners, and nonsteroidal anti-inflammatory agents. Others are characterized as gonadotropin-releasing hormone releasing hormone (GnRH) agonists, progesterone receptor agents, estrogen receptor agents, and antifibrinolytics. Because the mechanism of action is the progesterone it contains, we include the levonorgestrel (LNG) intrauterine device (IUD) as a progesterone medication in this review.
GnRH agonists down-regulate ovarian production of estrogen and progesterone and decrease stimulation of hormone receptors. This “medical menopause” decreases fibroid growth, promotes uterine involution, and reliably produces amenorrhea. This improves bulk symptoms, bleeding and the anemia associated with fibroids. Estrogenic add-back therapy may be used with a GnRH agonist to offset unwanted side effects such as hot flashes, vaginal dryness, and decrease in bone density. GnRH agonists include the injectable leuprolide, goserelin (an implant) and triptorelin.
Progesterone receptor agents modulate progesterone activity. Mifepristone competitively binds to the intracellular progesterone receptor, blocking the effects of progesterone and reducing fibroid size. Two things may limit its use: Mifepristone exhibits antiglucocorticoid activity, and only physicians with a prescriber’s agreement with the manufacturer can obtain the drug in the United States.34 Ulipristal acetate is a selective progesterone receptor modulator that is structurally similar to mifepristone, but has less antiglucocorticoid activity. 35-37 It has been FDA cleared since 2010 for emergency contraception. Ulipristal is cleared in Europe for long term medical management and preoperative therapy for fibroids. Levonorgestrel-IUD releases 20 µgr of levonorgestrel daily. It reduces bleeding by inhibiting endometrial proliferation.
Estrogen receptor agents: Selective estrogen receptor modulators bind to estrogen receptors to mimic or block estrogen activity, and have differential effects across tissue types (e.g., bone, brain, liver). Tamoxifen was introduced to block estrogen action in the treatment of breast cancer, but has estrogen–like effects on the uterus. Raloxifene has estrogen-like effects on bone, but anti-estrogen effects in the breast and uterus. It is used to treat osteoporosis and prevent breast cancer, and reduce fibroid size.
Combined hormonal replacement treatment (HRT): The transdermal estradiol patch plus a progestin can be used to reduce menopausal symptoms in women with fibroids. Combined birth control pills can be used to reduce bleeding and pain in pre-menopausal women.
Antifibrinolytics: Tranexamic acid improves blood clotting and is used to reduce heavy menstrual bleeding and to minimize postoperative blood loss.
Procedures
We considered those interventions that can typically be conducted in an office or as same-day surgery as procedures. These include uterine artery embolization or occlusion, high intensity focused ultrasound (HIFU) and radiofrequency fibroid ablation.
Uterine artery occlusion and embolization are techniques to interrupt the blood supply to uterine fibroids, which causes infarction and cell death within the fibroid, thus reducing fibroid size and symptoms. Uterine artery embolization (UAE) involves placement of a catheter through a blood vessel in the groin, using techniques similar to cardiac catheterization. Selected arteries are then blocked by introducing an embolization agent to close off the blood flow to the fibroid(s). UAE is an interventional radiology procedure, usually performed as an outpatient in an imaging suite. This procedure is an option for women who wish to avoid surgery, are poor candidates for surgery, or who wish to retain their uterus. It is not currently recommended for women who wish to have future pregnancies
Uterine artery occlusion is an older, less selective technique to directly occlude the main uterine vessels with sutures or coagulation at the time of open or laparoscopic surgery. Generally, occlusion is more invasive (requiring general anesthesia and an operating suite) and less selective than embolization. In one study, the authors describe “occlusion” as the use of vascular coils placed via uterine artery catheterization, which does not require surgery.38
High intensity focused ultrasound (HIFU), guided by ultrasound or MRI, directs a focused ultrasound beam to the fibroid. This induces thermal destruction of the target tissue. When MRI is used, the procedure is conducted in an MRI suite using a system that integrates real-time MRI and thermometry with an ultrasound unit specially designed to focus ultrasound waves. In 2004, the FDA approved one system (Magnetic Resonance Guided Focused Ultrasound (MRgFUS) for ablation of uterine fibroid tissue in pre- or perimenopausal women with symptomatic uterine fibroids with a uterine size of less than 24 weeks.
Radiofrequency ablation uses a laparoscopic approach to map fibroids with ultrasound, which are then ablated with an instrument that delivers the radiofrequency energy into the fibroid. One system is FDA cleared for use in the United States.
Surgery
We classify more invasive interventions that are typically performed in an operating room or require at least a brief hospital stay as surgical approaches. These include endometrial ablation, myomectomy, and hysterectomy.
Endometrial ablation is a procedure that destroys (ablates) the uterine lining (endometrium) using one of these techniques: laser, radiofrequency, thermal balloon, electricity (cautery, roller-ball), freezing, or microwave. The goal of endometrial ablation is to reduce or eliminate uterine bleeding. Pregnancy is not recommended after endometrial ablation, and tubal occlusion may be performed in conjunction with the procedure.
A myomectomy excises the fibroid(s) and repairs any defect in the uterine wall, while preserving the uterus. For this reason, myomectomy is an option for women who desire future pregnancies or who wish to retain their uterus. After myomectomy, fibroids could recur, which could lead to subsequent intervention(s).39 The surgical approach may be through an open abdominal incision (laparotomy) or a smaller open incision (minilaparotomy). A laparoscope can be used to remove the fibroid(s) through small incisions in the abdominal wall (laparoscopic) or a hysteroscope can be used to reach the fibroid(s) through the cervix (hysteroscopic). Myomectomy can be completed with or without a morcellator. Myomectomy can also be combined with endometrial ablation or uterine artery embolization.
Hysterectomy- the complete surgical removal of the uterus- is a definitive treatment for symptomatic fibroids in women who have completed childbearing. Hysterectomy does not require removal of the fallopian tubes and ovaries. Surgery that removes the entire uterus plus fallopian tubes and ovaries is properly called “total hysterectomy with bilateral salpingooophorectomy.” Surgery that leaves the uterine cervix intact is called supracervical hysterectomy. The surgical approach may be through an open abdominal incision (laparotomy), though the vagina (vaginal) or with the use of a laparoscope (laparoscopic). The open incision may be reduced in size (minilaparotomy). The laparoscopic procedure may be exclusive (total laparoscopic hysterectomy), or may include a vaginal procedure (laparoscopic assisted vaginal hysterectomy). Hysterectomy procedures can be completed with or without a morcellator.
Additional Management Concerns
Although it is not a separate procedure, it is important to discuss morcellator use for fibroid removal. Morcellation reduces the fibroid tissue to smaller fragments that can then be removed through smaller incisions. For several decades, power morcellators have been used to facilitate hysterectomy and myomectomy via less invasive laparoscopic approaches. Fragments can be removed directly through a port or using a flexible bag system that can then be removed through a port. One technique creates the fragments inside the bag system before removal. Several morcellation devices have FDA approval; all currently are included in a 2014 FDA safety communication that advises against using power morcellators “in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids” due to the risk of disseminating cancer in women with occult leiomyosarcoma. The FDA estimated the risk of occult leiomyosarcoma to be 20 (range: 11 to 38) per 10,000 women undergoing surgery for presumed fibroids.40,24 As a result of this advisory, women and surgeons are choosing more invasive treatments for fibroid removal, with the attendant increases in costs, risk of harm, and recovery time.41,42
Leiomyosarcomas are rare: an average of 1,600 new cases occur in the United States each year.43 However, they have poor outcomes with an average 5-year survival of 36 percent if cancer has spread to the pelvis and not isolated to the uterus. The primary means of dissemination of leiomyosarcoma is believed to be hematogenous. More than half of women with leiomyosarcomas develop distant metastasis before local recurrence in the pelvis, and most progress to higher stage disease regardless of order of spread.44,45
If the leiomyosarcoma is disrupted during removal, both visible and microscopic particles may be spilled. If spillage worsens stage and survival, then removing a leiomyosarcoma by power morcellation would have a poorer outcome than using scalpel morcellation, and both of these would be inferior to removing the uterus and tumor intact.
Scope and Key Questions
Scope
To best inform clinical decisions about care we focused on evidence from randomized trials that assessed effectiveness of currently used interventions for women of any age with fibroids. We also sought to identify factors that might modify likelihood of favorable results or harms from treatments. We included studies evaluating medications, procedures, and surgeries for the management of uterine fibroids. For expectant management, we summarize data from women who were followed within trials without active intervention. In order to inform women and providers, accurate estimates are needed regarding the prevalence of leiomyosarcoma and risks of dissemination after morcellation.
This review does not cover preoperative adjunctive treatments such as GnRH agonists or intraoperative techniques, like use of cell savers that have established effectiveness as preoperative or adjunctive interventions to minimize blood loss or otherwise improve short-term operative outcomes. We also do not review trials comparing operative devices (such laparoscopic instruments for ligation versus cautery of the uterine vessels) if the trial included only intermediate outcomes. Except in the context of factors assessed at the time of imaging that may help identify risk of dissemination of leiomyosarcoma, we do not address diagnostic accuracy of imaging. We did however seek to examine conventional fibroid characteristics as assessed by imaging and how they relate to achieving desired outcomes.
Key Questions
Key Question 1. What is the comparative effectiveness (benefits and harms) of treatments for uterine fibroids, including comparisons among these interventions?
Key Question 2. Does treatment effectiveness differ by patient or fibroid characteristics (e.g., age; race/ethnicity; symptoms; menopausal status; imaging characteristics; vascular supply to fibroids; or number, size, type, location, or total volume of fibroids)?
Key Question 3. What is the risk of encountering a leiomyosarcoma for masses believed to be uterine fibroids at the time of myomectomy or hysterectomy?
Key Question 4. Does survival after leiomyosarcoma differ by patient or fibroid characteristics (e.g., age; race/ethnicity; symptoms; menopausal status; imaging characteristics; vascular supply to fibroids; or number, size, type, location, or total volume of fibroids) or by surgical approach to fibroid morcellation?
Analytic Framework
The analytic framework provides context for our Key Questions (KQs) and illustrates the population, intermediate outcomes, final health outcomes, and interest in a specific set of harms that guided the literature search and synthesis of evidence (Figure 1).
Figure 1
Analytic framework. KQ = Key Question
Organization of This Report
The overall structure of the report arranges findings in order to address the most common questions of women and care providers, as follows.
1. What are the options for managing fibroids and what are typical outcomes? Meaning, if a woman chooses a type of intervention, how is that choice likely to turn out? Will fibroids change, will symptoms improve, will quality of life improve, and will she be satisfied with this choice? These questions are answered by arranging all the outcome data about a particular drug, procedure, or surgery together and showing the aggregate expectations for available outcomes such as change in fibroids or change in bleeding. When multiple studies included an outcome we used tables to summarize this data. When few studies addressed the outcome (such as future pregnancy outcomes, or harms), we address these outcomes in text. (KQ1a)
2. If a woman chooses an option, how likely is it that she will need additional intervention in the near future? We modeled subsequent intervention by category of initial intervention to address this question. We note that women choosing to participate in randomized controlled trials of different types of interventions may differ in key ways that cannot be defined from the literature (KQ1b).
3. What information is available that directly compares one type of intervention compared to other types of interventions? This question is best answered by review of truly comparative studies, for instance those that examine medication versus procedure, or procedure versus a particular surgery. If study data speak only to the question of choosing a dose, choosing a drug within a category, or choosing a surgical approach (e.g., laparoscopic vs. open) we included those studies in our summary of results for each category of intervention (KQ1c), as it primarily informs the first question above (i.e., effects from a given type of drug or surgery). In this section at the end of KQ1 we address genuine comparisons of different management approaches (Comparative Effectiveness Studies) because this is what women and care providers are considering. They are weighing whether one type of intervention is better on average than another choice, or if equivalent, do patient values and priorities make it easier to choose knowing they are equivalent.
4. Is there anything about a woman or her fibroids that can help determine what is likely to work well? We attempted to identify characteristics in the literature that may address this question (KQ2).
5. If a woman has a mass thought to be a fibroid, what is the likelihood that she has a leiomyosarcoma? Are there factors which would influence survival of a woman with leiomyosarcoma? We then address the risk of leiomyosarcoma (KQ3) and then present information about individual and fibroid characteristics and surgical approach that may modify leiomyosarcoma survival (KQ4).
- Introduction - Management of Uterine FibroidsIntroduction - Management of Uterine Fibroids
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