FDA guidance highlights inappropriate use of power morcellation, but concern about interpretation lingers

An FDA warning about the use of laparoscopic power morcellators to treat uterine fibroids has polarized the gynecologic oncology community.

The agency’s “immediately in effect” guidance warns against the use of morcellators in hysterectomies or myomectomies in the majority of women due to the potential that they can spread undetected uterine sarcomas.

Soon after the announcement, several large institutions — including Cleveland Clinic and Brigham and Women’s Hospital — stopped performing laparoscopic power morcellation. One leading manufacturer of the devices, Johnson & Johnson, pulled its products off the market.

Yet, intense debate rages among surgeons and clinicians about whether FDA intended for power morcellation to be abandoned entirely, or if the agency intentionally left its guidance vague enough to allow surgeons to perform the procedures in patients who provide informed consent.

“The box warning was expected, but there’s sort of a mixed interpretation,” R. Wendel Naumann, MD, director of minimally invasive surgery in gynecologic oncology at Levine Cancer Institute at Carolinas HealthCare System, told HemOnc Today. “On one hand, there are many patients who either weren’t appropriate or weren’t the best candidates for morcellation, and this guidance highlights that. But, there is some concern with the way it was interpreted by hospitals — and some physicians — who made it even more restrictive than the FDA intended for it to be. That’s how it has been interpreted, but I’m not sure that’s how it was necessarily meant to be interpreted.”

HemOnc Today spoke with several surgeons and clinicians about whether the risks of the minimally invasive surgery outweigh the benefits, as well as the potential that power morcellation or the devices used during the procedure can be improved to reduce patients’ risks. Experts also offered their opinions about the quality of the data on which the FDA warning was based, and whether the agency’s guidance extends too far — or fails to go far enough — to protect women’s health.

Data discrepancies

Power morcellation entails the insertion of a tiny instrument with a rapidly rotating blade that grinds up uterine fibroids and allows for their removal via a laparoscope. It allows for a smaller incision, quicker recovery period, fewer side effects and lower rate of morbidity than open surgery.

However, the FDA guidance — issued on Nov. 24, 2014 — recommends manufacturers of laparoscopic power morcellators include a boxed warning to acknowledge the risk that undetected leiomyosarcomas or other malignancies within uterine tissue can be disseminated throughout a woman’s pelvic and abdominal cavities during morcellation, increasing risks for morbidity and mortality.

The guidance also recommends to contraindications be included on product labeling.

One recommendation is to contraindicate laparoscopic power morcellators for women who are peri- or postmenopausal, as well as those who are candidates for en bloc tissue removal through the vagina or mini-laparotomy incision. A majority of the estimated 50,000 to 100,000 women who undergo laparoscopic procedures for hysterectomy annually in the United States meet these criteria.

The guidance also recommends contraindication of the devices during gynecologic surgery in which the tissue to be morcellated is either suspected or known to be cancerous.

Based on quantitative analysis of available data, the FDA estimated that approximately 1 in 352 women who undergo hysterectomy or myomectomy for presumed benign fibroids has an unsuspected uterine cancer, and that 1 in 498 has an unsuspected leiomyosarcoma.

Jason D. Wright, MD, chief of the division of gynecologic oncology and associate professor of obstetrics and gynecology at Columbia University Medical Center, and colleagues conducted a separate study and reached a similar conclusion.

“We looked at more than 36,000 women,” Wright told HemOnc Today. “We found the risk of an occult malignancy as 1 in 368, and that aligns pretty closely with the FDA estimates.”

Other retrospective analyses — including one performed by Elizabeth A. Pritts, MD, an obstetrician–gynecologist at and medical director of Wisconsin Fertility Clinic in Middleton, Wisc., and colleagues — reached a far different conclusion.

“Their initial research identified 41 papers, of which they found nine that were evaluable. Our initial search identified 4,864 papers, and we identified 133 with data that were evaluable,” Pritts said in an interview. “I think the way they ran their meta-analysis was incomplete.”

The FDA data suggests an occult leiomyosarcoma would be found in 2.01 of every 1,000 surgeries, whereas results of the study by Pritts and colleagues — which she presented in November at the American Association of Gynecologic Laparoscopists Global Congress on Minimally Invasive Gynecology — suggested an occult leiomyosarcoma would be found 0.12 in every 1,000 surgeries.

“Because I was so intimately involved in our statistics, because we had a professional statistician and because we had so many people involved in the analysis of our data, I think our data are closer,” Pritts said. “They may not be perfect, but I think they are the best evidence we have right now, and they are certainly better than theirs because ours are more inclusive. We found more information than they found.”

Naumann made a similar presentation, results of which indicated mortality from laparoscopic hysterectomy with power morcellation — taking possible dissemination of undiagnosed leiomyosarcomas into account — was 0.077%, compared with 0.085% with abdominal hysterectomy.

A ‘silly’ debate

The Society of Gynecologic Oncology — which has more than 1,800 members, primarily gynecologic oncologists — issued a statement in July 2014 to the FDA’s Obstetrics and Gynecology Medical Devices Advisory Committee suggesting the FDA based its recommendation in studies included in a retrospective case series with “low-quality evidence.”

“The FDA would not approve a device using such low-quality retrospective data,” the statement read. “It is concerning that the FDA would now consider banning a device with a similar low level of evidence.”

Critics of the FDA guidance say better research could have been performed and allowed for clinicians to interpret subsequent guidance differently.

“I am very concerned that, although we all recognize that some recognition and statement needed to be made by the FDA, this statement in many ways falls short and fails to evaluate some of the more current data that are being produced, all of which is remarkably consistent,” Jubilee Brown, MD, associate professor in the department of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “As we saw at the AAGL meeting, multiple different investigators — even from different countries — are showing the same thing: The prevalence rate is very likely less than that quoted by the FDA. Even when we use the data the FDA has, we still are able to model and predict that minimally invasive surgery — even with the risk of morcellation — is safer for the patient in general when appropriately worked up and counseled than open surgery.”

Not everyone shares that opinion.

David Mutch, MD, professor of obstetrics and gynecology and division chief of gynecologic oncology at Washington University School of Medicine in St. Louis, called the debate over the numbers “silly.”

“We have gotten into this mentality that if it’s minimally invasive, it has to be better,” Mutch told HemOnc Today. “That’s not so.”

Patients who undergo open hysterectomy typically spend a day or two more in the hospital — and have a couple extra weeks of recovery — compared with those who undergo the laparoscopic procedure.

“I get that, but if I do that on a thousand 38-year-olds and they stay in the hospital an extra couple days and have a decreased risk for metastatic disease, and then I have just one patient who I morcellate and I contribute to her death at age 38, I have to do a lot of those procedures to make up for that in the teeter-totter of life,” Mutch said.

Risk vs. reward

The FDA guidance — and the multiple interpretations of the data on which the provisions are based — re-energized the risk-vs.-reward debate about power morcellation.

“There’s always a risk,” Naumann said. “The problem is, we always want to make things zero-risk, and we just can’t do that. Every time we get on an airplane, we know there’s a risk of a crash. We do everything we can to prevent it, but it’s going to occur. The question becomes: Is that risk worth the benefit of flying? What are the alternatives? Well, the fact is, driving is not as safe as flying. We have an unrealistic fear of airplane crashes, which is why people are afraid to fly.”

The same is true with cancer, Naumann said.

“When you look at the average mortality from morcellation in the model we created, it’s just over 1 in 10,000 cases, which is lower than the mortality of the hysterectomy itself, and it’s lower than the difference between abdominal hysterectomy and vaginal hysterectomy,” Naumann said.

Still, some surgeons do try to eliminate risk, regardless of how low the likelihood for complications might be.

Mark Wakabayashi, MD, chief of gynecologic oncology surgery at City of Hope does not use power morcellators. When necessary, he morcellates manually to reduce risk.

Yet, a potentially bigger problem is being overshadowed, Wakabayashi said.

“I used to counsel patients [about morcellation] before this all came out,” Wakabayashi said. “If you look at the numbers, we have ovarian cancers where people are offering cystectomies and are spilling the contents, and nobody counsels them. The incidence is even higher than [with morcellation]. It’s interesting how we’re focusing on [morcellation] but [cystectomies] are an even bigger problem.”

Even when morcellation is not used, cancerous uterine fibroids can pose threats. If a fibroid is removed intact and it turns out to be malignant, the chance of recurrence — even for stage I disease — is about 50%.

“[Cases in which] somebody who had a morcellation and had the tumor spread throughout the abdominal cavity are very rare,” Wakabayashi said. “So, I think what the FDA came out with is very reasonable, because they didn’t say, ‘Don’t use it on anybody.”

That is an important distinction, as many surgeons suggest power morcellators still could be viable in certain instances.

“We need to be really careful that the pendulum doesn’t swing too far to one side,” Wright said. “Certainly, there’s a risk with morcellation. That risk is now being recognized and we are better defining that risk. But the corollary to all this … is that morcellation probably does allow some women to undergo a minimally invasive procedure who would otherwise require a laparotomy. That is undoubtedly beneficial.”

Menopausal status

About half of the leiomyosarcomas occur in post-menopausal women, and most other uterine cancers occur in post-menopausal women, Brown said.

“If we are able to eliminate morcellation as an option for post-menopausal women, that [alone] will substantially decrease the risk of an undetected malignancy,” she said.

When Pritts read the literature, she was “pretty shocked” how prevalent power morcellation was among postmenopausal women prior to the FDA’s guidance.

“That reflects poorly on the gynecologists,” Pritts said. “We shouldn’t be doing this.”

It is primarily for that reason that Mutch has taken such a strong stance against power morcellation. Surgeons often use it out of convenience rather than practicality, he said.

“They want to do it minimally invasively and that’s their little shtick,” Mutch said. “Sadly, I think perhaps they don’t want to look at the data — or they can’t look at it in an objective way. I don’t know why. The data seems pretty clear. Though rare, the dissemination of sarcoma must be part of informed consent.”

Most clinicians agree postmenopausal women should not undergo power morcellation, and they also agree that premenopausal women are at significantly lower risk, but considerable questions remain with regard to perimenopausal women, who comprise the majority of the population eligible for power morcellation.

The FDA didn’t clearly define “perimenopausal,” instead leaving that part of its guidance open to interpretation.

Some clinicians suggest “perimenopausal” status can begin at age 40 years; others contend it is closer to 45 years. Yet, no conclusive data exist to establish an optimal cut-off between premenopausal and perimenopausal.

“The need for a national registry is huge,” Brown said. “We need to do better in the United States for our patients. It is amazing that, in this country, we only have single-institution retrospective studies or big database studies that are very non-specific and don’t capture a full population. We have no way to know specific outcomes of every person who undergoes this procedure.”

Risk-reduction strategies

The debate about power morcellation also has prompted conversations about whether steps could be taken to make the procedure safer, ensuring it remains accessible to patients who understand their potential risks and provide informed consent.

Some of those steps can be taken pre-operatively, yet development of a gold standard for diagnosing something as rare as leiomyosarcoma in uterine fibroids is still a ways off.

Some clinicians favor imaging, whereas others prefer biopsy. Published data suggests the rate of detection of leiomyosarcoma by endometrial biopsy is 38% to 86% (median, 62%).

“That’s really substantial,” Brown said. “No, it’s not a perfect test, and no, it’s not going to pick up every single leiomyosarcoma. But if every person is appropriately screened for menopausal status and with pre-operative biopsy, that will substantially decrease the rate of undetected leiomyosarcoma in patients undergoing morcellation.”

Pritts agreed, but also said MRI can be useful, too. Her retrospective analysis identified 60 reports of leiomyosarcomas. Of those, 56 were diagnosed preoperatively.

Another strategy that had been considered to improve safety was the addition of a containment bag to the end of the morcellator. In that scenario, fibroids would be morcellated inside the bag in the abdominal region to prevent the potential spread of the tissue.

A study of containment bags began last summer at Brigham and Women’s Hospital, but there was controversy because it was initiated without an Investigational Device Exemption, an FDA license that allows for clinical trials with high-risk devices.

Once the FDA issued its guidance, the study was halted.

“If someone develops a morcellator that allows you to put the specimen in the bag and a device that can morcellate it without injuring the bag and can pull it out without any spill, that would be perfect,” Wakabayashi said. “But it has to be something that anybody who does it can reproduce.”

Most clinicians who spoke with HemOnc Today said they would like to see continued study of morcellation with containment bags. Still, some emphasized the greatest concern isn’t necessarily with morcellators themselves, but rather with those who are using them.

“In the six studies we identified, there were 81 leiomyosarcomas that were removed and only three were removed in a power fashion,” Pritts said. “It’s not the power morcellator. … I trained before the morcellator was available, so I have many tricks to remove these fibroids, but some of the newer surgeons only know how to use the morcellator to remove fibroids or large specimens. Basically, this is going to turn all of these cases into either vaginal cases or abdominal cases.”

There are other ways to spread a leiomyosarcoma without a power morcellator, but the FDA only has an authority over the device itself. That is why it is in the spotlight, Pritts said.

“The problem is still with us, though,” she said. “If we do an abdominal case and we use a single-tooth tenaculum and we puncture the leiomyosarcoma during the removal of the uterus, that may indeed spread the cancer cells. [The FDA] only addresses the power morcellation instrument and they don’t address anything else. They don’t address hand morcellation, and they can’t because they are only in charge of the equipment that we utilize.”

More data needed

The FDA guidance has created a line in the sand, of sorts, with some surgeons and clinicians lining up on each side.

Some, like Naumann, say they will continue to use the device.

“As an oncologist, I often have to take out the uterus intact because I can’t chop it up or I’m worried about the condition that I am treating,” Naumann said. “I am used to getting rather large uteri out through the vagina, and that can certainly be done. … If you can get the uterus out through a very small incision or through the vagina, you should. It’s very reasonable.”

Others, like Wright, said it would be prudent to pause before considering power morcellation. There still is not enough information to make a decision about the appropriate approach, even if available criteria suggest some patients’ risk is far lower than others.

“I think it’s still an open question,” Wright said. “The big problem with morcellation is this procedure diffused into practice with really minimal data. Now, you are seeing a lot of backlash against the entire technique. I think we need more data to study this to find those groups of women who benefit from this technology.”

Despite her concerns about the FDA guidance, Pritts said some positives could emerge from the recent attention — and criticism — power morcellation has received.

“This may push the medical community — in particular our colleagues in radiology — to really work on finding a pre-operative, diagnostic modality so that we are never taking these patients with leiomyosarcomas to surgery,” Pritts said. – by Anthony SanFilippo

References:

FDA. Immediately in effect guidance document: Product labeling for laparoscopic power morcellators. 2014. Available at www.fda.gov/downloads/MedicalDevices DeviceRegulationandGuidance GuidanceDocuments/UCM424123.pdf. Accessed on Jan. 25, 2015.

FDA. Laparoscopic power morcellation during uterine surgery for fibroids. 2014. Available at: www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/ObstetricsandGynecologyDevices/UCM404148.pdf. Accessed on Jan. 28, 2015.

Pritts EA. J Minim Invasive Gynecol. 2015;22:26-33.

Society of Gynecologic Oncology. Statement of the Society of Gynecologic Oncology to the Food and Drug Administration’s Obstetrics and Gynecology Medical Devices Committee concerning safety of laparoscopic power morcellation. 2014. Available at: www.sgo.org/wp-content/uploads/2014/04/SGO-Testimony-to-FDA-on-Power-Morcellation-FINAL.pdf. Accessed on Jan. 28, 2015.

The American College of Obstetricians and Gynecologists. Power morcellation and occult malignancy in gynecologic surgery. 2014. Available at: www.acog.org/Resources-And-Publications/Task-Force-and-Work-Group-Reports/Power-Morcellation-and-Occult-Malignancy-in-Gynecologic-Surgery. Accessed on Jan. 28, 2015.

Wright JD. JAMA. 2014;312:1253-1255.

For more information:

Jubilee Brown, MD, can be reached at jbbrown@MDAnderson.org.

David Mutch, MD, can be reached at mutchd@wudosis.wustl.edu.

R. Wendel Naumann, MD, can be reached at wnaumann@mac.com.

Elizabeth A. Pritts, MD, can be reached at epritts@wisconsinfertility.com.

Mark Wakabayashi, MD, can be reached at mwakabayashi@coh.org.

Jason D. Wright, MD, can be reached at jw2459@columbia.edu.

Disclosure: Brown, Mutch, Naumann, Pritts, Wakabayashi and Wright report no relevant financial disclosures.

Should power morcellation still be an option for premenopausal women?

Power morcellation should be an option for this patient population.

In general, I am supportive of the majority of the FDA recommendation. In the setting of known or suspected cancers, morcellation should not be undertaken. But, it is important to offer people a variety of options and to make sure that there is an informed consent process.

Among premenopausal women who have fibroids, the chance of there being an undiagnosed malignancy is very, very low. With appropriate informed consent, women should have the option to consider morcellation. If the choice is between a large laparotomy or morcellation, I believe informed women should be able to make this choice themselves.

Sometimes people forget that if you do not perform morcellation, it often means that you have to make a big incision in someone’s abdomen. When you make a laparotomy, there is a much higher risk of certain complications, such as blood clots, surgical site infections, higher risks for bleeding, and often prolonged cases that require additional doses of antibiotics, which can increase risk for Clostridium difficile infections. All of these complications have an associated risk for morbidity and mortality. I don’t think you can look at morcellation in isolation without talking about the alternatives to morcellation and the risks of those alternatives.

In the FDA statement, the contraindication of morcellation in perimenopausal women is very vague. It does not give surgeons a lot of guidance, and there is some frustration about that. Perimenopausal can mean a very wide range of things. The majority of women who are going to need hysterectomies are probably going to be perimenopausal, so it is difficult to interpret that recommendation.

People have a right to choose. I know we do not want to do harm to patients, which is why there are opponents to morcellation, but if we trade morcellation for open laparotomy, we may be harming many more patients to prevent the morcellation of a cancer (projected to happen in 1 of every 350 to 1,000 cases).

Finally, we have an ethical principle of autonomy: People should get to decide how they want to live their lives and, to some extent, how they want their health care to be. I believe in patient autonomy for making an informed choice when they know the risks up front. Ultimately, more research is need to identify cancers prior to surgery so that minimally invasive surgery and its significant benefits can be offered to as many patients as possible.

 

Barbara Ann Goff, MD, is professor of obstetrics and gynecology and director of the division of gynecologic oncology at UW Medicine in Seattle. She also is an affiliate researcher at Fred Hutchinson Cancer Research Center. She can be reached at Seattle Cancer Care Alliance at South Lake Union, 825 E. Lake Ave., East Seattle, WA 98109; email: bgoff@uw.edu. Disclosure: Goff reports no relevant financial disclosures.

It is difficult to argue that laparoscopic power morcellation would be safer in premenopausal patients than peri- or post-menopausal patients.

There has been recent concern about the use of laparoscopic power morcellation for the removal of uterine tissue, notably in the treatment of uterine fibroids.

The FDA provided an updated communication on Nov. 24, 2014, that noted that laparoscopic power morcellators are “contraindicated for removal of uterine tissue containing suspected fibroids in patients who are peri- or post- menopausal or are candidates for en bloc tissue removal.” In addition, patients with tissue suspected or known to contain malignancy should not undergo laparoscopic power morcellation.

One of the concerns about power morcellation is an increased risk for intra-abdominal recurrence and worsening prognosis, which is supported by several retrospective studies and a recent meta-analysis (Bogani G. Gynecol Oncol. 2014;doi:10.1016/j.ygyno.2014.11.011). This meta-analysis found a fourfold increase in intra-abdominal recurrence rate and a 2.5-fold worsening of OS in patients who underwent morcellation.

It is then interesting to note that the FDA states that some premenopausal women who desire to maintain fertility or desire to maintain their uterus may use laparoscopic power morcellation as an “acceptable therapeutic option.” Although uterine malignancies — especially leiomyosarcomas — do tend to affect women at a median age of 50 years, it would be difficult to argue that laparoscopic power morcellation would be any safer in pre-menopausal patients as compared with peri- or post-menopausal patients.

Leiomyosarcoma is a rare disease that is difficult to diagnosis preoperatively, and the age at diagnosis reported in various studies tends to indicate a wide range of age distribution (30s to 70s).

Certainly, high-quality studies are needed to investigate the safety of laparoscopic power morcellation in the premenopausal population, and health care providers should still offer careful counseling of the risks and alternative options.

 

Ernest Han, MD, PhD, is an assistant professor and surgeon in the division of gynecologic oncology at City of Hope. He can be reached at City of Hope, 1500 E. Duarte Road, Duarte, CA 91010; email: ehan@coh.org. Disclosure: Han reports no relevant financial disclosures.