FDA Advisory Panel Voices Concern About Morcellation Risk

Miriam E. Tucker

July 14, 2014

SILVER SPRING, Maryland — A US Food and Drug Administration (FDA) advisory panel has voiced support for greater restrictions on the use of laparoscopic power morcellators (LPMs) in uterine fibroid surgery, while leaving the door open for industry to create safer devices.

On July 11, the second day of a 2-day meeting, the Obstetrics and Gynecology Devices Advisory Committee answered specific questions from the FDA about how the agency might address the newly appreciated risk that when LPMs are used to remove presumably benign fibroids during minimally invasive procedures, the morcellation process could inadvertently disseminate unsuspected malignant tissue, resulting in the "upstaging" of the tumor and worsening of the patient's prognosis.

The first LPM was FDA-cleared in 1991, and the first with a gynecologic indication became available in 1995. The FDA is now considering reclassifying the devices into a more restrictive regulatory category, and possibly adding a "black box," the highest level of product warning. The meeting was convened for the FDA to elicit the panel's input on those and other issues.

On the first day of discussion, the panel struggled to make sense of "very weak" data informing the risk, but generally agreed that the odds of a woman with uterine fibroids having an unsuspected cancer were likely higher than had been assumed in the past.

Day 2 began with often-emotional testimony from a series of patients and family members of patients who had received morcellation and subsequent advancement of a previously unrecognized tumor. Several of the women said they had been assured by their obstetricians/gynecologists that they did not have cancer, and that they had not been informed of the risks of the procedure.

Referencing that testimony in their deliberations, panel members stressed, at a minimum, the importance both of a thorough workup of women with uterine fibroids before any surgical intervention, and of informed consent.

Opposing Views

Several physicians also delivered public testimony, some in support of keeping morcellation, others calling for a ban.

Jubilee Brown, MD, director of gynecologic oncology at the University of Texas MD Anderson Cancer Center in Houston, spoke on behalf of the American Association of Gynecologic Laparoscopists (AAGL). She said that LPMs allow for up to 100,000 women a year to undergo minimally invasive surgery and that if the devices were to be banned from the market, these women would be forced to undergo riskier open procedures.

She presented findings from an AAGL analysis suggesting mortality rates of 0.085% per year for open hysterectomy vs 0.077% for laparoscopic hysterectomy using power morcellators, assuming a 1 in 585 prevalence of occult leiomyosarcoma and accounting for all other known risks of both procedures.

According to the analysis, converting all women currently undergoing hysterectomy for uterine fibroids from laparoscopic to open surgery would result in an additional 17 women per year dying from hysterectomy. "Let us improve, but not abandon, power morcellation," Dr. Brown said.

However, Amy J. Reed, MD, PhD, an anesthesiologist at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, rejected the assumption that taking away power morcellators would mean that all woman undergoing hysterectomy would automatically end up having full abdominal procedures.

"Laparoscopic surgery involves opening a small incision. Morcellation is shredding up tissue. Other branches of surgery operate laparoscopically without morcellation. They do so by making an incision appropriate for the mass in question," she told the panel.

Dr. Reed, whose case of tumor upstaging after LPM was the first to be filed with the FDA, in December 2013, and who subsequently received wide media attention, noted that morcellation also interferes with pathological diagnosis of uterine tissue and may lead to misdiagnosis. "Morcellation is bad medicine," she said.

Can Morcellation Be Made Safer?

Panel members generally agreed that although factors such as patient age, race, and magnetic resonance imaging (MRI) and endometrial biopsy can assist in determining which women with presumed benign fibroids are at greater risk for an unsuspected sarcoma, none can be relied on to definitively rule out the possibility, even when used in combination.

Referring to use of MRI, Robert F. Mattrey, MD, vice chairman of research and professor of radiology at the University of California, San Diego, said, "I think when a fibroid looks benign (ie, dark, well circumscribed)...it is benign. But the majority of the difficulty comes when fibroids don't look that way. It's not that we can't diagnose leiomyosarcoma, it's just that a good percent of fibroids could look like leiomyosarcoma, and to distinguish those 2 would be difficult."

Nicolas Wentzensen, MD, PhD, senior investigator at the National Cancer Institute Division of Cancer Epidemiology & Genetics, Hormonal and Reproductive Epidemiology Branch, Bethesda, Maryland, said he and colleagues recently conducted a large study to investigate this question, pooling uterine sarcoma data from 15 large population-based studies. Although they found some risk factors compared with control patients, "the magnitude of those would not be useful for assigning risk categories," he said.

Panel members were also unconvinced that the use of specimen bags to contain the tissue during the morcellation procedure could entirely mitigate the risk from an occult tumor, and in fact, may rupture or tear with the morcellation blade, and also can impair the surgeon's ability to visualize the field. Some panel members felt that certain types of specimen bags or techniques used with the bags might mitigate the risk, but that more study is needed.

Keith B. Isaacson, MD, medical director of the Newton-Wellesley Hospital Center for Minimally Invasive Gynecologic Surgery in Newton, Massachusetts, said, "I think that if you're going to morcellate, and it can be done safely in a bag, that should be encouraged. The caveat is doing more work to study the bags, and study the techniques.... I still believe intuitively that it will likely mitigate the risk of upstaging the tumor if you morcellate within a containment system such as a bag."

However, Craig D. Shriver, MD, colonel, Medical Corps, United States Army; professor of surgery, Uniformed Services University of Health Sciences; and chief, General Surgery Service, Walter Reed National Military Medical Center, Bethesda, Maryland, countered, "That's the problem. After 20 years, all we have is intuition. There's no evidence that bags or any containment devices prevent the outcome we're trying to prevent…. That's a great question for a clinical trial with next-generation containment and extraction technology."

Risk vs Benefit

Asked to name specific patient types for whom the benefit of LPM might outweigh the risks, Dr. Isaacson described a hypothetical young woman with 2-year history of infertility, multiple symptomatic uterine fibroids, and no risk factors for leiomyosarcoma  who wants a uterine-sparing procedure to preserve her fertility. He said he would do a complete workup including biopsy, MRI, and ultrasound, and would offer that woman the option of an open myomectomy or laparoscopic approach with morcellation.

In that scenario, "The minimally-invasive approach will result in fewer adhesions and a better reproductive outcome," Dr. Isaacson said.

For hysterectomy, however, Carol L. Brown, MD, director, Office of Diversity Programs in Clinical Care, Research, and Training at Memorial Sloan Kettering Cancer Center, New York City, said, "I really can't think of a clinical situation.... My bias, in trying to completely mitigate the risk for spreading undiagnosed cancer, is to not morcellate."

She added, "There are other options for the treatment of fibroids that don't involve invasive surgery at all that I would steer a patient towards...such as uterine artery embolization, focused ultrasound, birth control pills, [intrauterine devices], etc. There's a whole set of things you go through before you get to invasive surgery to treat fibroids, and we shouldn't lose that in this discussion."

Black Box

A majority of panel members endorsed the idea of placing a black box warning on the devices advising of the occult cancer potential and other risks associated with LPMs, as well as separate labeling for physicians and patients and consent requirements beyond the usual routine signatures to ensure both sides understand the risks.

In response to a panel member's question, the FDA staff confirmed that the informed consent process would have to take place in situations where the need for morcellation was not known before the surgery.

Dr. Brown pointed out that the documentation would have to be available outside the sterile packaging of the morcellator device, as that is not opened until the patient is already asleep on the table. "I think that would be a benefit, because it would make the surgeons think more carefully ahead of time who you're going to use it in.... It would force everybody to think about it ahead of time."

FDA panel members are vetted for conflicts of interest and waivers granted if necessary. No waivers were granted for participants of this hearing. However, the Wall Street Journal reported that one panel member had stepped down before the meeting after FDA determined that he had accepted fees from a device manufacturer. Dr. Brown and Dr. Reed have disclosed no relevant financial relationships.

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