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Experts provide an update on current and emerging drugs and procedures as an alternative to myomectomy for uterine leiomyomas.
Uterine leiomyomas (fibroids) are benign smooth muscle neoplasms that affect up to 70% of women over their lifetime.1 They are the most common primary indication for hysterectomy and account for over $34 billion in health care costs annually in the United States.2,3 Common symptoms of fibroids include heavy or prolonged menstrual bleeding, pelvic pain, pressure-related symptoms, and bladder and bowel disturbance.1
For the woman who wants to manage symptoms while maintaining her uterus or improve her fertility outcome, myomectomy has been considered the gold standard.4 However there are substantial risks to myomectomy with overall reported complications in surgeon-reported series of 3% to 16% and 25% in analysis of an insurance claims database.5,6 Common complications include hemorrhage and transfusion (5% risk), and damage to other organs requiring a subsequent procedure (25%).5,6 Also for women desiring future pregnancy, many myomectomy procedures commit women to a cesarean delivery in future pregnancies, further increasing surgical morbidity.
In addition to complications, surgery can be expensive and require a significant recovery period with estimates from the literature of 15 to 30 days, and shorter recoveries in women who undergo endoscopic procedures.5 Moreover, because of the high rate of new fibroid formation, many women undergo multiple surgeries. Rates of reintervention with a second uterine-sparing procedure are 22% and with a hysterectomy are 16.7% with 5-year follow-up based on claims data.6 With our increasing knowledge of fibroid biological development and technological innovation, we now have multiple alternatives to traditional surgery, including medical and less invasive procedural management that will be considered here. The Agency for Healthcare Research and Quality recently produced a comprehensive evidence report on fibroid therapies which comprehensively assesses this topic.5
Combined estrogen/progestin and progestin-only oral contraceptives (OCs) have historically been seen as first-line therapy for fibroids due to their safety profile, low cost and reliable contraception. The levonorgestrel intrauterine system (LNG-IUS) is also being increasingly used for heavy or prolonged menstrual bleeding (AUB-L utilizing FIGO nomenclature); it also provides reliable contraception that does not require daily use.
Surprisingly, high-quality data to support OCs or LNG-IUS for treatment of symptomatic fibroids are limited, as many studies do not have a proper comparison group.5 Observational data have demonstrated support for OCs. However, one randomized trial of 58 women demonstrated significantly decreased AUB-L in those treated with LNG-IUS when compared to OCs (mean menstrual blood loss decreased by 77.5% by extraction of blood from sanitary products and 34.5% by menstrual pictogram.7) Overall, we are still in need of better evidence demonstrating the superiority of contraceptive steroids.
Progesterone receptor modulators
Although classically estradiol (E2) has been thought of as the key hormonal influence of fibroid pathophysiology, both scientific investigation and clinical use of progesterone receptor modulators (PRMs) for fibroid treatment now suggest that progesterone is the major hormonal influence.8 In contrast to contraceptive steroids, PRMs have been studied in multiple randomized controlled trials (RCTs) and have shown moderate evidence for symptomatic relief, including reduction in fibroid size and decreased AUB-L and pain.9 Mifepristone and ulipristal acetate have been studied most commonly and there are 14 RCTs with more than 1200 participants demonstrating an improvement in quality of life.5,9 Thus, PRMs are widely used as first-line therapy outside the United States but are not approved by the US Food and Drug Administration (FDA).
While original reports focused safety concerns on endometrial changes following continuous use of PRMs, rare but serious liver injury has recently become the focus of safety with ulipristal acetate treatment as currently used in intermittent courses separated by shedding of the endometrium.10 New guidance had been issued by the European Medicines Agency (EMA) based on serious events involving the liver, in some cases requiring liver transplantation, occurring in approximately 1:100,000 women. This guidance requires screening women for liver dysfunction with both history and liver function tests before, during, and after treatment. Finally, the guidelines recommend restricting ulipristal acetate to one treatment course in women who are eligible for surgery.
Gonadotropin-releasing hormone (GnRH) agonists/antagonists
GnRH agonists exert their effect by having a higher potency and longer half-life than endogenous GnRH, which when used in a recurring manner leads to prolonged binding to its receptor.11 This initially leads to an increase in FSH and LH secretion from the anterior pituitary and subsequently a flare in estrogen production followed by suppression. GnRH agonists have shown a reduction in fibroid volume and improvement in AUB-L along with an improvement in quality of life.5 Concerns with long-term treatment with GnRH analogues stem from evidence showing a decrease in bone mass after 4 to 6 months of therapy along with significant hypoestrogenic side effects that include vasomotor symptoms, atrophic vaginitis, and insomnia, which occurs due to the hypothalamic-pituitary-ovarian axis blockade.11,12 The GnRH agonist leuprolide acetate is FDA-approved for short-term use in treatment of uterine fibroids in conjunction with iron for preoperative treatment. Add-back therapy with different modalities (raloxifene, conjugated estrogens, estriol) can be useful in preserving bone density but there is limited evidence that this leads to improvement in hypoestrogenic symptoms.11 In addition, after discontinuation of therapy, fibroid growth will typically resume, leading to a return in original size or beyond.13
In contrast to GnRH agonists, GnRH antagonists exert their effect by competing for the GnRH receptor and thus have a more rapid onset without the initial flare. GnRH antagonists for fibroids demonstrated a significant reduction in tumor volume but require daily treatment.11 A new generation of oral GnRH antagonists used either alone or with hormonal add-back therapy is in clinical trials for treatment of uterine fibroids. A recent noninferiority trial demonstrated more rapid onset of amenorrhea with an oral GnRH antagonist (relugolix) and similar reductions in AUB-L and uterine volume when compared to leuprolide acetate.14 An RCT evaluating add-back therapy with a second oral GnRH antagonist (elagolix) demonstrated a continued reduction in AUB-L and add-back therapy reduced negative effects on bone mineral density.15
Uterine artery embolization
Uterine artery embolization (UAE) utilizes a single small incision in the groin and radiographic guidance of catheters and embolic agents to the uterine arteries bilaterally. Thus multiple fibroids can be targeted simultaneously. UAE requires sedation and typically is performed as an overnight admission or same-day procedure.
Multiple RCTs have demonstrated the efficacy of UAE in women with fibroids. The quality of evidence has been high for a significant volume reduction that continued for 5 years and improvements in AUB-L along with moderate evidence for an improvement in quality of life.5 When compared to hysterectomy and myomectomy, risk of transfusion with UAE was drastically reduced (OR 0.07, 95% CI, 0.01-0.52). Women undergoing UAE also recovered more rapidly and had fewer major complications, but more minor complications requiring no or nominal therapy, including overnight admission for observation, were noted when UAE was compared to hysterectomy but not when compared to myomectomy.16 In the RCT between UAE and hysterectomy, postembolization and vaginal discharge were the most frequent minor complication following UAE and infection and hemorrhage the most common following hysterectomy; the median length of stay was 1 day for UAE and 5 days for hysterectomy possibly affecting readmission for observation.17
Concerns regarding UAE are associated with a higher rate of subsequent surgical intervention with estimates of 7% for myomectomy and hysterectomy versus 15% to 32% for UAE.5 However, studies have not reported whether failures of UAE are due to concomitant diseases such as adenomyosis, which is also treated with hysterectomy but not uterine-sparing approaches. In a study based on insurance claims, the chance of a complication requiring a subsequent procedure was substantially higher following myomectomy compared to UAE in a propensity-matched group (24.6 vs. 18.1%, HR 1.38 (95% CI, 1.25-1.52).6
Another concern of UAE is the potential impact on ovarian reserve, fertility, and pregnancy complications. A systematic review that compared obstetric outcomes in women following UAE to age-matched women with fibroids who did not undergo myomectomy reported an increased risk of miscarriage (OR 2.8, 95% CI, 2.0-3.8), cesarean delivery (OR 2.1, 95% CI, 1.4-2.9), and postpartum hemorrhage (OR 6.4, 95% CI, 3.5-11.7), but no difference in other obstetric outcomes.18 Studies have demonstrated there is no significant difference in ovarian failure rates at long-term follow-up and there is very-low-level evidence that there is a decrease in fertility following UAE compared to myomectomy.16 Finally, there are numerous reports of successful pregnancy following UAE and some national guidance recommending UAE for fertility preservation.19
High-intensity focused ultrasound ablation (HIFU) is a noninvasive method that uses ultrasound energy to create coagulative necrosis in a well-defined area through the anterior abdominal wall. HIFU can be performed under magnetic resonance imaging (MRI) or ultrasound guidance; however, only the device that uses MRI guidance is approved in the United States. Both procedures are performed on an outpatient basis with sedation and no incisions.
Overall, HIFU has been shown to be effective for decreasing fibroid size/volume.5 Recent investigation has shown that other important patient outcomes are also improved. A large cohort study compared 1353 women undergoing ultrasound-guided HIFU to hysterectomy (N=472) or myomectomy (N=586).20 Quality of life improved more quickly after HIFU compared to surgical intervention and HIFU had only 0.2% major adverse outcomes compared to 12.6% in the surgical cases (P < 0.001). Despite multiple differences in patient demographics between the treatment groups, with the patients undergoing HIFU being younger, better educated, and wealthier compared to the surgery groups, the authors concluded there is less morbidity when patients undergo HIFU compared to surgery.20 A case control study analyzing approximately 10,000 women who underwent HIFU demonstrated successful rates of ablation with a mean volume ablation rate of 83.1% ± 15.6% (range, 25%-100%) for patients with fibroids.21 The authors found that with conscious sedation and analgesia there were minimal side effects and very few severe complications.21 Case series have documented successful pregnancy outcomes following MRgFUS.22,23
The Fibroid Interventions: Reducing Symptoms Today and Tomorrow (FIRSTT) study analyzed patients randomized into UAE or MRgFUS groups and a parallel group declining randomization.24 Both groups had improved fibroid symptoms and quality of life for up to 2 years but improvement was significantly better for women who underwent UAE and risk of needing another fibroid procedure was higher (HR 2.81, 95% CI, 1.01-7.79, P = .047) for women undergoing MRgFUS.24
Radiofrequency ablation (RFA)
Introduced in 1999, laparoscopic, intra-abdominal-guided radiofrequency ablation (RFA) is another surgical modality developed to be less invasive. Benefits of this procedure include ease of use as it does not require laparoscopic suturing and there is no dissemination of tissue in the abdomen, which can occur with laparoscopic hysterectomy/myomectomy. A RCT by Bruker et al. demonstrated a shorter hospital stay and decreased blood loss when comparing RFA to laparoscopic myomectomy.25 While this is an attractive option we have limited evidence about long-term outcomes for RFA and it still requires a laparoscopy. A transcervical, intrauterine sonography-guided RFA device has been studied and is approved for use outside the United States but is not FDA-approved.26
In the not too recent past, surgical intervention represented the only strategy for symptomatic and/or large fibroids. With our growing appreciation of high fibroid incidence and burden, we are continuing to develop less-invasive strategies to improve symptoms and patient quality of life. Overall, there is good evidence that demonstrates that GnRH agonists and PRMs result in reduction of fibroid volume and improvement in quality of life for women with fibroids. UAE has also been shown to reduce uterine and fibroid volume with improvement in quality of life with more data needed to verify the procedure’s safety in patients planning to conceive in the future. While OCs have been first-line therapy in the past, there is a paucity of data supporting their benefit and, therefore, other strategies should be explored. Lastly, HIFU has been shown to reduce fibroid volume but more rigorous studies are needed to determine long-term outcomes and assess fertility following treatment.
The authors report no potential conflicts of interest with regard to this article.