BBI Contributing Editor
PHILADELPHIA, Pennsylvania This year's annual clinical meeting of the American College of Obstetricians and Gynecologists (ACOG; Washington), the organization's 52nd, was held here in early May. This is the largest gathering of women's healthcare physicians in the U.S., with thousands of ob-gyns, experts in related fields and exhibitors participating in the meeting, which includes clinical and educational seminars, postgraduate courses, poster sessions, paper presentations and updates on current issues. With improvements in women's health as a goal, advancements in gynecologic treatments, including those for fibroids, were discussed at this year's meeting. With 13 different procedures to treat fibroids and the number of manufacturers providing products to serve those procedures numbering well in excess of that, the exhibit hall was a veritable "fibroid fair." As seen in Table 4, the market opportunity is sizable.
Fibroids, benign growths in the uterus, can cause pelvic pain, infertility, pressure and excessive bleeding that often disrupts a normal lifestyle. Uterine fibroids occur in 25% to 50% of women, although some believe the prevalence may be as high as 80%. Some researchers contend that fibroids exist in all women ages 30-40, but that some of those women never become symptomatic and are never counted among the number of patients who seek help.
Fibroids are cited as the reason for nearly 40% of the 650,000 hysterectomies performed each year in the U.S. Until recent years, the most popular treatment for chronic symptomatic fibroids, following medical therapy, was hysterectomy, a major surgery that includes a hospital stay and long recovery.
On the opposite end of the treatment spectrum has been medical management, involving the use of a gonadotropin-releasing hormone (GnRH) such as Lupron, Zoladex or Synarel, that threw the patient into premature menopause with all its associated side effects. These drugs stop estrogen production, which then causes the fibroids to shrink, since it is recognized that estrogen feeds fibroids. Even if the medical therapy is successful, patients are only allowed to be on it for six months due to the side effects, which include bone loss, and shortly after cessation of the GnRH agonist, the fibroids usually come back. This form of hormone therapy today often is used as a first line of defense to shrink the fibroids prior to surgery, in order to reduce blood loss during the myomectomy.
Neither option surgery or hormones is optimal, but until recently there have been no other choices for patients suffering from symptoms caused by fibroids. Today's thinking is not to remove an otherwise healthy organ, the uterus, but rather to treat the fibroids and with this new thinking many new ways of treating fibroids have developed (see Table 5 below).
The next less-invasive organ-sparing surgical procedure is a myomectomy, or the surgical removal of the fibroids one by one, which can be performed either by open surgery, laparoscopic surgery or hysteroscopically (placing a scope through the uterus). All of these procedures require hospitalization and a recovery time. Because the uterus is not removed, the patient may be able to maintain her fertility with the surgical approaches; adhesions often develop which can later cause a uterine rupture during pregnancy or delivery. While the hysteroscopic approach eliminates the potential for adhesions, it is estimated that only 6% to 10% of gynecologists have the training and skill set to perform a hysteroscopic myomectomy. With all three of these procedures, the surgeon must remove each fibroid independently, usually leaving behind very small ones that frequently grow into larger ones later, necessitating a repeat procedure.
Two new technologies developed for myomectomy but not yet FDA-approved are cryomyolysis from American Medical Systems (Minnetonka, Minnesota) and radiofrequency (RF) ablation from RITA Medical Systems (Mountain View, California). Each of these methods mimics a myomectomy in that the fibroid must be removed one-by-one, they are less invasive than open surgery, and use different energy modalities to excise the tissue with one, freezing the tissue, the other thermally ablating the tissue with radiofrequency energy. In a poster presentation titled "Laparoscopic Cryomyolysis: A One-Year Follow-up," Errico Zupi, MD, of Tor Vergata University of Rome (Rome), showed that at one year, laparoscopic cryomyolysis dramatically decreased the size of fibroids.
Another poster presentation by Linda Bradley, MD, of the Cleveland Clinic Foundation (Cleveland, Ohio), demonstrated that for submucosal fibroids, which account for only about 5% of all fibroids, microwave endometrial ablation was effective. A microwave endometrial ablation system has been manufactured by Microsulis (Boca Raton, Florida), and although no other studies using endometrial ablation (EA) devices have been performed to determine the effects of EA on fibroids, it is assumed that only submucosal fibroids could be ablated because EA systems only ablate the inner lining of the uterus. Many types of endometrial ablation products are currently on the market (see The BBI Newsletter, May 2003) and will not be discussed in the context of fibroids at this time, since it appears that only Microsulis has performed fibroid-specific studies, and only submucosal fibroids could be treated.
Uterine artery embolization is an interventional procedure that cuts off the blood flow to fibroids, thus "starving them to death" by injecting small plastic particles into the blood vessels that supply blood to the fibroids. This procedure is minimally invasive, can be performed on an outpatient basis, has a short recovery time and is much less costly than a hysterectomy. It also leaves a healthy uterus in place with potential for pregnancy. Why, then, has it not been popularized? Because of a very difficult referral pattern that did not develop in a friendly manner. The patient is diagnosed by a gynecologist who then needs to refer the patient to an interventional radiologist (IR), who then should refer the patient back to the originating gynecologist for after-care. This referral pattern usually does not occur. In a recent survey, only 38% of gynecologists even mentioned UAE to patients with fibroids. Initially many patients went directly to the IR, and when the post-embolectomy pain occurred the IR called the gynecologist to "fix it." That adversarial pattern has not changed much, with a stagnant 30,000 UAE procedures being performed annually, when early forecasts predicted the number eventually climbing to 100,000. There also have been reports of the tiny particles migrating to other parts of the body and pregnancy outcomes following UAE as being not as healthy as without UAE.
Temporary occlusion of the uterine artery is a non-surgical technique developed by Vascular Control Systems (San Juan Capistrano, California) that provides the benefits of UAE without the disadvantages. The procedure acts similarly as that of UAE in that it occludes blood vessels that supply blood to fibroids but is designed for gynecologists, using Doppler ultrasound, to non-invasively and temporarily occlude the uterine arteries. It utilizes a vaginal approach and can be done in an outpatient setting, with little recovery time and less pain than UAE. Clinical trials are currently under way in the U.S. as well as Canada with a controlled market launch anticipated for early 2005, following 510(k) approval. Patients maintain their uterus and return to normal menses, allowing one to think that normal pregnancies could be achieved.
One of the least-invasive and most cost-effective measures being used for fibroids is the Mirena IUD, an intrauterine device (IUD) impregnated with levonorgestrel that acts like the other GnRH agonists, but is released regionally in the uterus. This puts the fibroids in a state of "suspended animation" until the device is removed. Although success using another levonorgestrel-releasing IUD to treat menorrhagia caused by fibroids was reported in the March 2004 issue of the Journal of the American Medical Association, the product is approved for use as a contraceptive only in the U.S.
Fibroids are most prevalent in the 30- to 40-year-old category, and as more women are delaying childbearing until those years, fertility is becoming a big issue in the treatment for fibroids, unlike for previous generations, when by the time fibroids became symptomatic; the woman had completed her childbearing and was more accepting of a total hysterectomy. In a poster presentation titled "Pregnancy Outcomes Following Uterine Artery Embolization vs. Laparoscopic Myomectomy," Jay Goldberg, MD, clinical assistant professor at Jefferson Medical College (Philadelphia, Pennsylvania), said that women who become pregnant following uterine artery embolization for fibroids may be at a higher risk for pre-term delivery, spontaneous abortion and postpartum hemorrhage, compared to women who have had laparoscopic myomectomy. He did not study women who had a ligation or temporary occlusion of the uterine arteries.
As noted in Table 5, some of the options for fibroid treatment allows the woman to maintain her fertility (to varying degrees) while others do not. For women trying to maintain their fertility, their choice may translate into a higher complication rate during pregnancy. Dr. Moises Lichtinger, chairman of the department of ob/gyn at Holy Cross Hospital (Fort Lauderdale, Florida), said he feels that fibroids may compete with an implanting embryo for uterine blood supply and that is why women with fibroids have a more difficult time conceiving and maintaining a pregnancy. He said that it is not inconceivable that a procedure, such as temporary uterine artery occlusion, that can eliminate fibroids and then return the uterus to normalcy may in fact be "fertility enhancing" and be used as a first option in future fertility efforts.
Since fibroids grow in multiples, any procedure that can address all the fibroids at one time, instead of individually addressing each one, will cut down on costly operating time. Global treatments such as uterine fibroid embolization (UFE), uterine artery ligation and temporary occlusion of the uterine artery can address all the fibroids at one time.
An interesting approach to non-invasively ablating uterine fibroids was demonstrated by InSightec (Haifa, Israel) a company that was established in 1999 as a joint venture between GE Medical Systems (now GE Healthcare; Waukesha, Wisconsin) and Elbit Medical Imaging (Tel Aviv, Israel). The system uses a combination of real-time magnetic resonance imaging (MRI) for treatment planning and guidance, and focused ultrasound (FUS) to thermally ablate fibroids totally non-invasively. The patient lies over a water bath in which the ultrasound source is positioned. The patient and the water bath are positioned within the MR for imaging. The ultrasound is focused similar to that of using a magnifying glass to focus the sun's energy on a single spot. The focused light energy does not create heat along its way. However, in the focal point, the condensed energy rapidly raises the temperature in the fibroids to the point of tissue destruction. InSightec received CE certification for use of its ExAblate 2000 for the treatment of uterine fibroids and has 17 systems installed worldwide. The company submitted its premarket approval application in January and was scheduled to go before an FDA advisory panel early this month. While this treatment has the potential to replace major surgery, the downside is the cost of the equipment, a limit to the total volume of fibroid tissue that can be ablated in a single session and the fact that treatment duration is currently three to four hours. Nonetheless, the presence of this unit on the exhibit floor felt like rocket science. It certainly is the least invasive, and may play a role in the future treatment of fibroids.