Author Insights: Cancer Risks of Uterine Procedure Probed

Jason D. Wright, MD, of Columbia University College of Physicians and Surgeons, and colleagues found that 1 in 386 women who undergo morcellation for uterine fibroids have undetected uterine cancer. Morcellation may inadvertently spread cancerous tissue throughout the abdomen. Image: Columbia University

Jason D. Wright, MD, of Columbia University College of Physicians and Surgeons, and colleagues found that 1 in 368 women who undergo morcellation for uterine fibroids have undetected uterine cancer. Morcellation may inadvertently spread cancerous tissue throughout the abdomen. Image: Columbia University

More than 1 in 360 women who undergo a surgical procedure to treat noncancerous growths called fibroids that develop from the muscular tissue of the uterus have underlying cancer that may spread as a result of the surgery, suggests a study published in JAMA today.

A minimally invasive procedure to treat fibroids by removing the uterus, laparoscopic hysterectomy, involves use of electric or power morcellators to cut uterine tissue into pieces small enough to be removed through small incisions. This approach to treating uterine fibroids spares women the need for more invasive surgery, which involves longer recovery times. But there has been increasing concern that this less invasive procedure also may inadvertently spread cancerous tissue throughout the abdomen of women who have undiagnosed uterine cancer. Spreading such cancerous tissue can “upstage” the cancer and may lead to worse outcomes. Recently, a JAMA Viewpoint and JAMA news article outlined the concern and the need to apprise women of the benefits and risks of the procedure.

In April, the US Food and Drug Administration (FDA) warned against using morcellation to treat fibroids because of the potential risks. At the time, the agency estimated that 1 in 350 women who undergo surgical treatment for fibroids have undetected uterine cancer. Today’s study bolstered the FDA’s estimate.

The study examined records for 232 882 women who underwent a minimally invasive hysterectomy, including 36 470 (15.7%) whose surgery involved morcellation. The researchers found 99 cases of uterine cancer among the women who underwent morcellation, suggesting a prevalence of 1 cancer per every 368 women. Older women were at greater risk than those younger than 40 years of having underlying cancer.

Jason D. Wright, MD, chief of the division of gynecologic oncology and associate professor at Columbia University College of Physicians and Surgeons, discussed the findings with news@JAMA.

news@JAMA: Why did you decide to do the study?

Dr Wright: Once the controversy about electric power morcellation for uterine fibroids started to grow, we looked at the available data. We found little data describing the risks of underlying cancer in women undergoing morcellation.

news@JAMA: How do your findings compare with other studies?

Dr Wright: Most of the prior studies were not specific to morcellation. They just looked at cancer rates among those undergoing hysterectomy. Our study looked specifically at patients undergoing morcellation and found that the risk of having an underlying uterine cancer was 1 in 368. It’s fairly consistent with what the FDA estimated.

news@JAMA: What do your findings add to the current debate about the risks of morcellation?

Dr Wright: It’s one of the first large-scale studies looking at power morcellation. It provides a national estimate of the risk of morcellation. It’s important information for patients and clinicians so they can gauge the risks and benefits. We also looked at precancerous changes in the uterus and the risk factors and predictors of cancer. Age was a strong risk factor. If you are older, you are much more likely to have an underlying cancer.

news@JAMA: About a week ago, an FDA advisory panel concluded there is unlikely to be any way to reduce the cancer-associated risks of morcellation. What’s your reaction to that?

Dr Wright: Our study didn’t specifically address the risk of spreading cancer. The question is, if you undergo morcellation, how much does it increase your risk? Does it affect survival? There is not much objective data about techniques to reduce morcellation risk.

news@JAMA: What do you think women and physicians should know?

Dr Wright: The most important finding is that there is definitely a risk associated with underlying cancer or precancerous changes in women undergoing morcellation. It’s hard to detect prior to surgery. Morcellation may allow some women to undergo a minimally invasive surgery. Our study gives patients and physicians an estimate of the cancer risks so they can make an informed decision.

Physicians Group Discourages Routine Pelvic Exam

A new guideline suggests women may skip the annual pelvic examination if they have no symptoms of concern. Image: © iStockphoto.com/jenjen42

A new guideline suggests women may skip the annual pelvic examination if they have no symptoms of concern. Image: © iStockphoto.com/jenjen42

Most women are accustomed to the uncomfortable ritual of having a yearly pelvic examination. But a new guideline from the American College of Physicians (ACP) suggests it may be time to make the procedure a thing of the past for women without any symptoms of concern. The recommendation does not apply to pregnant women or those who have signs of illness.

Women should continue to receive routine cervical cancer screening, according to the ACP, but the procedure should include only visual inspection and swabbing of the cervix, not a physical evaluation of the uterus. The ACP cautioned, however, that a pelvic examination is advisable for women who have vaginal discharge, abnormal bleeding, pain, urinary difficulties, or sexual dysfunction.

The recommendation is likely to be extremely controversial. The American College of Obstetricians and Gynecologists continues to recommend routine pelvic examinations as part of an annual well-woman visit. However, the ACP argues that there is no clear evidence of benefit, so the harms of fear, anxiety, embarrassment, pain, discomfort, and false positives outweigh the potential benefit of routinely conducting pelvic examinations on apparently healthy women.

The recommendation is based on the ACP’s review of the evidence on pelvic examinations from 1946 through 2014. The review found that pelvic examinations on apparently healthy women rarely detect noncervical cancer or other treatable conditions and that the practice didn’t improve patient outcomes.

“[Routine pelvic examination] rarely detects important disease and does not reduce mortality and is associated with discomfort for many women, false-positive and -negative examinations, and extra cost,” said Linda Humphrey, MD, a coauthor of the guideline.

An accompanying editorial noted that it’s not clear whether the ACP’s recommendation will change the practice of obstetrician/gynecologists. The editorialists note that the evidence base is limited and many gynecologists believe pelvic examinations help detect noncancerous masses, but they argue that clinicians should be aware of both the potential harms of pelvic examinations and the uncertainty surrounding benefits of the procedure.

FDA Warns Against Procedure Used in Removing Fibroids

Image: JAMA, ©AMA

Image: JAMA, ©AMA

The US Food and Drug Administration (FDA) is discouraging the use of a surgical technique often used during minimally invasive surgery to treat uterine fibroids because it poses a risk of inadvertently spreading cancer cells from an undetected uterine tumor.

The focus of the agency’s concern is the use of medical devices called electric or power morcellators during laparoscopic (minimally invasive) surgery to remove the uterus or fibroids, noncancerous growths that develop from the muscular tissue of the uterus. The morcellator is used to cut uterine tissue into fragments that can be removed through the small incisions used in laparoscopic surgery. But in a safety communication released today, the FDA said that, based on its analysis of currently available data, 1 in 350 women who are treated for fibroids with surgery—a hysterectomy or myomectomy (fibroid removal)—is found to have an unsuspected uterine sarcoma, such as a leiomyosarcoma.

“If power morcellation is performed in women with unsuspected uterine sarcoma, there is a risk that the procedure will spread the cancerous tissue within the abdomen and pelvis, significantly worsening the patient’s likelihood of long-term survival,” the FDA said. “For this reason, and because there is no reliable method for predicting whether a woman with fibroids may have a uterine sarcoma, the FDA discourages the use of laparoscopic power morcellation during hysterectomy or myomectomy for uterine fibroids.”

As a JAMA news feature published earlier this year noted, in recent months, some critics of the procedure have said that use of the technique may be too risky, whereas others said that more research on risks was needed before banning it outright. The Society of Gynecologic Oncology issued a statement in December about the potential risks and the concern that no reliable methods exist to distinguish benign growths from cancers before they are removed. Some prominent US medical centers, including Brigham and Women’s Hospital, Massachusetts General Hospital, and the Cleveland Clinic issued statements stressing the importance of counseling patients about the procedure and potential risks.

An estimated 600 000 hysterectomies are performed annually in the United States. According to the National Institutes of Health, more than 200 000 hysterectomies are performed each year for uterine fibroids.

Various therapies, including drugs, surgical removal of individual fibroids, and hysterectomy, are used to treat symptoms caused by fibroids, which may include heavy or prolonged menstrual bleeding or pelvic pressure or pain. “Health care providers and patients should carefully consider available alternative treatment options for symptomatic uterine fibroids,” the FDA said.

***

For more information:

Critics of Fibroid Removal Procedure Question Risks It May Pose for Women With Undetected Uterine Cancer. Hampton, T. JAMA. 2014;311(9):891-893.

Evaluating the Risks of Electric Uterine Morcellation. Kho, KA and Nezhat, CH. JAMA. 2014;311(9):905-906.

 

 

 

 

 

 

 

 

 

 

 

New Tissue Engineering Studies Answer Important Questions

New research describes how 3-dimensional scaffolds were created to form engineered vaginal tissue. (Image: Wake Forest Institute for Regenerative Medicine)

New research describes how 3-dimensional scaffolds were created to form engineered vaginal tissue. (Image: Wake Forest Institute for Regenerative Medicine)

Researchers have for the first time used engineered tissue to successfully reconstruct noses and build implantable vaginas, according to 2 studies published today.

Reporting online in The Lancet, investigators at the University of Basel in Switzerland described reconstructive procedures on 5 patients aged 76 to 88 years with non-melanoma skin cancer on the nose. The patients had substantial amounts of skin and cartilage removed from the alar wings surrounding the nostrils. The tissue served as the basis to create grafts. Usually surgeons take grafts from the nasal septum, ear, or ribs to reconstruct the nose. But those procedures are invasive, painful, and may result in complications.

So the investigators developed an alternative method. They cultured patients’ nasal septum cartilage cells with growth factors for 2 weeks before seeding them onto collagen membranes. Culturing for 2 more weeks produced cartilage 40 times larger than the original biopsy. Grafts were individually shaped for each patient and implanted. One year after the reconstructions, all 5 patients were satisfied with their ability to breathe and their nose’s cosmetic appearance. None had any adverse effects.

“The engineered cartilage had clinical results comparable to the current standard surgery,” research team leader Ivan Martin, PhD, said in a statement. “The method opens the way to using engineered cartilage for more challenging reconstructions in facial surgery such as the complete nose, eyelid, or ear.”

The second study described techniques used to engineer laboratory-built vaginas for 4 teenage girls with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. The condition is a rare genetic disorder in which the vagina and uterus don’t develop properly or at all.

Researchers in the United States and Mexico employed techniques similar to those used in the nose reconstructions. They extracted cells from each girl’s external genitals, expanded the cells, and seeded them onto biodegradable scaffolds sewn into 3-dimensional vagina-like shapes. The scaffolds were tailor-made for each girl.

Surgeons implanted the scaffolds by creating a canal in the pelvis and suturing the engineered vagina in place. After follow up for 8 years, the implants functioned the same as native vaginal tissue. All the patients’ responses to a Female Sexual Function Index questionnaire showed normal sexual function, including desire and pain-free intercourse. They reported no adverse effects.

In an accompanying editorial, researchers at University College London in England said the studies show that over time, the engineered tissues functioned the same as native tissue. The vaginal scaffold study also showed that the engineered tissues responded well as the girls developed into women and that the body’s own new blood vessel growth may be sufficient even for large engineered tissue structures.

“These authors have not only successfully treated several patients with a difficult clinical problem, but addressed some of the most important questions facing translation of tissue engineering technologies,” Martin Birchall, MD, one of the editorial’s coauthors, said in a statement.

 

Author Insights: Two Doses of HPV Vaccine Reduce Genital Wart Risk

Lisen Arnheim-Dahlström, PhD, of the Karolinska Institutet in Stockholm, Sweden, and her colleagues provide evidence that 1 or 2 doses of the human papillomavirus vaccine may provide some protection against the development of genital warts. Image: Karolinska Institutet

Lisen Arnheim-Dahlström, PhD, of the Karolinska Institutet, and her colleagues found that 1 or 2 doses of the human papillomavirus vaccine provide some protection against genital warts. Image: Karolinska Institutet

Just 2 doses of the human papillomavirus (HPV) vaccine reduced the risk of young women developing genital warts, although 3 doses provided even greater protection, according to a study published in JAMA today.

A 3-dose regimen of HPV vaccine is recommended for girls and young women in the United States and many other countries to reduce their risk of developing cervical cancer and other HPV-related conditions, such as genital warts. But the multiple-dose regimen, costs, and other concerns have dampened HPV vaccine’s uptake. According to the US Centers for Disease Control and Prevention, in 2012 only one-third of US teens received all 3 doses of the vaccine and a little more than half received at least 1 dose.

Some previous studies have suggested that fewer than 3 doses of the HPV vaccine may also reduce the effects of the virus to some extent. Now, Lisen Arnheim-Dahlström, PhD, of the Karolinska Institutet in Stockholm, Sweden, and her colleagues provide evidence that 1 or 2 doses may provide some protection against the development of genital warts, or condylomas.

The researchers followed a cohort of more than 1 million Swedish females between the ages of 10 and 24 years between 2006 and 2010. They identified 20 383 new cases of genital warts, including 322 that occurred among individuals who received at least 1 dose of the HPV vaccine. The most protection was offered by the 3-dose regimen, which was associated with incidence of 459 fewer cases of genital warts per 100 000 person-years. A 2-dose regimen was slightly less effective, reducing cases by 400 per 100 000 person-years. Receiving 1 dose of HPV vaccine reduced cases by 384 per 100 000 person-years.

Dr Arnheim-Dahlström spoke with news@JAMA about the results.

news@JAMA: Why did you decide to look at genital warts as an end point?

Dr Arnheim-Dahlström: Condyloma represents the earliest measurable disease outcome for the HPV vaccine, as the incubation time for condyloma is much shorter than for precancerous lesions of the cervix or cervical cancer.

news@JAMA: Do you think your findings strengthen the case that 2 doses might be enough to protect against HPV-related disease?

Dr Arnheim-Dahlström: The immunogenicity trials show that 2 doses mount high antibody responses against HPV types in the vaccine, and our study shows that receiving 2 doses was associated with substantial risk reduction. However, it is important to further evaluate this finding with cervical cancer as the end point.

news@JAMA: Are your results generalizable to the United States?

Dr Arnheim-Dahlström: Approximately 30% of the targeted population [adolescent girls aged 13-17 years] were vaccinated, which I think is comparable to the US vaccination rates. The result from our study is probably generalizable to the situation in the United States.

news@JAMA: Could HPV infections contracted before vaccination have affected your findings?

Dr Arnheim-Dahlström: It may be so that some study participants had an infection prior to vaccination. We do not know this because we could not measure HPV status in this study. However, we included into our statistical model buffer periods to account for [prior] infections.

news@JAMA: What questions remain to be answered?

Dr Arnheim-Dahlström: Will 3 doses still offer protection when measured with longer follow-up time? Will the results be different or the same when we study girls who received the vaccine when they are younger, 10 to 12 years? What about when higher vaccination coverage and herd immunity may be achieved? Further, what will the result be when we study outcomes such as precancerous lesions of the cervix.

news@JAMA: What would you say is the main take-home message?

Dr Arnheim-Dahlström: There are several important messages. This study is an important complement to the clinical trials, as they have data only on immunogenicity by dose level and not disease outcomes. Further, our population-based study may also be more generalizable to the more diverse populations actually getting vaccinated.

Still, the most important outcomes—precancerous lesions and cervical cancer—need to be studied as well. Clinicians and patients should stick to the recommended dose schedule until new recommendations are made.

Growing Concern Over Procedure for Hysterectomies and Fibroid Removal

Image: JAMA, ©AMA

Posted today on JAMA:

Two articles have been posted that examine a procedure for hysterectomies and fibroid removal known as electric uterine morcellation, which involves the use of an instrument for fragmenting fibroids or uterine tissue into smaller pieces for easier removal through a laparoscopic port. There is growing concern that this procedure has important risks, including:

  • Inadvertent dispersion and ectopic implantation of small tissue fragments during the procedure, causing symptoms and illness requiring intervention;
  • Dissemination of fragments of undetected and confined malignant tumors throughout the abdominal cavity, upstaging the cancer;
  • Injuries or death caused by damage from the blade of the instrument to organs.

A Viewpoint (available at this link) and JAMA Medical News & Perspectives article (available at this link) discuss the risks, potential alternatives, informed consent process and recommendations for addressing this issue.

Even a Single Dose of the HPV Vaccine May Offer Lasting Protection

Mahboobeh Safaeian, PhD, of the National Cancer Institute, and her colleagues found that even a single dose of human papillomavirus vaccine can induce a lasting response. Image: National Cancer Institute.

Mahboobeh Safaeian, PhD, of the National Cancer Institute, and her colleagues found that even a single dose of human papillomavirus vaccine can induce a lasting response. Image: National Cancer Institute.

Just a single dose of a 3-dose vaccine against 2 strains of the human papillomavirus (HPV) may protect a woman for years, according to surprising results from a clinical trial in Costa Rica. The findings raise the possibility that fewer doses may be a feasible approach to protecting women, particularly in the developing world where costs and logistics can make multidose vaccinations hard for women to complete.

The vaccine is an important public health tool to protect women against infection with strains of the virus that may lead to cervical cancer. But the cost and the need for 3 doses of the vaccine have contributed to poor uptake of the vaccination in the United States. These barriers to vaccination are greater in the developing world, where women may be even more sensitive to costs or may face logistical challenges to getting repeated doses. With less access to screening and treatment for cervical cancer, women in the developing world are more at risk of death from cervical cancer, which is the most common cause of cancer-related death among women in the developing world.

But the findings by Mahboobeh Safaeian, PhD, an investigator at the National Cancer Institute, and her colleagues offer preliminary evidence that a less arduous HPV vaccination regimen may be possible. The researchers analyzed the HPV-16– and HPV-18–specific antibody levels in women who had received 1 dose of the HPV-16/18 vaccine (78 women), 2 doses one month apart (140 women), 2 doses 6 months apart (52), or 3 doses (120 women) over 4 years*. They also analyzed antibody levels in blood samples from 113 women who tested positive for HPV infection at enrollment. All of the vaccinated women remained seropositive for HPV-16/18 at 4 years after vaccination, with the group that received 2 doses 6 months apart having levels comparable with the 3-dose group. Even the 1-dose group had antibody levels to HPV-16 and HPV-18 that were 9 and 5 times higher, respectively, than women who were infected at enrollment, and the 2-dose group had antibody levels 24 and 14 times higher, respectively, than those who were presumably infected naturally. The antibody levels in the 1-dose group stayed steady from 6 months to 4 years after vaccination.

Further studies will be necessary to confirm the findings and prove that the 1-dose antibody levels are sufficient to protect against cervical cancer. In the meantime, however, the findings may have important implications for vaccine developers. Safaeian and her colleagues noted that the durable antibody response they documented is more similar to the response to a live-attenuated vaccine rather than a protein-based vaccine, which requires frequent boosting.

“Our findings challenge previous dogma that protein subunit vaccines require multiple doses to generate long-lived responses,” Safaeian said in a statement.

*This blog has been updated to include information omitted in the original draft.