OBG Management

AN OPEN LETTER TO THE FDA ON MORCELLATION FOR PRESUMED UTERINE FIBROIDS
On December 8, 2015, 46 minimally invasive surgeons, gynecologic oncologists, and other experts spoke out in unison when they sent an open letter to the US Food and Drug Administration (FDA). They called into question the FDA’s estimate of the likelihood of occult leiomyosarcoma (LMS) and recommended continued use of power morcellation in appropriate cases.

An excerpt from this letter is published here. To read the letter in its entirety and the names of the signees, click here. 

Letter excerpt:

If abdominal hysterectomy is recommended to women with fibroids, will women be better off?
By focusing exclusively on the risk of LMS, the FDA failed to take into account other risks associated with surgery. Laparoscopic surgery uses small incisions, is performed as an outpatient procedure (or overnight stay), has a faster recovery (2 weeks vs 4–6 weeks for open surgery), and is associated with lower mortality and fewer complications. These benefits of minimally invasive surgery are now well established in gynecologic and general surgery.

Using published best-evidence data, a recent decision analysis¹ showed that, comparing 100,000 women undergoing laparoscopic hysterectomy with 100,000 undergoing open hysterectomy, the group undergoing laparoscopic surgery would experience 20 fewer perioperative deaths, 150 fewer pulmonary or venous embolus, and 4,800 fewer wound infections. Importantly, women having open surgery would have 8,000 fewer quality-of-life years.

A recently published study² found that, in the 8 months following the FDA safety communication, utilization of laparoscopic hysterectomies decreased by 4.1% (P = .005), and abdominal and vaginal hysterectomies increased by 1.7% (P = .112) and 2.4% (P = .012), respectively. Major surgical complications (not including blood transfusions) increased from 2.2% to 2.8% (P = .015), and the rate of hospital readmission within 30 days also increased from 3.4% to 4.2% (P = .025). These observations merit consideration as women weigh the pros and cons of minimally invasive surgery with morcellation versus open surgery.

Clinical recommendations
Recent attention to surgical options for women with uterine leiomyomas and the risk of an occult LMS are positive developments in that the gynecologic community is reexamining relevant issues. We respectfully suggest that the following clinical recommendations be considered:

• The risk of LMS is higher in older postmenopausal women; greater caution should be exercised prior to recommending morcellation procedures for these women.
• Preoperative consideration of LMS is important. Women aged 35 years and older with irregular uterine bleeding and presumed fibroids should have an endometrial biopsy, which occasionally may detect LMS prior to surgery. Women should have normal results of cervical cancer screening.
• Ultrasound or MRI findings of a large irregular vascular mass, often with irregular anechoic (cystic) areas reflecting necrosis, may cause suspicion of LMS.
• Women wishing minimally invasive procedures with morcellation, including scalpel morcellation via the vagina or mini-laparotomy, or power morcellation using laparoscopic guidance, should understand the potential risk of decreased survival should LMS be present. Open procedures should be offered to all women who are considering minimally invasive procedures for “fibroids.”
• Following morcellation, careful inspection for tissue fragments should be undertaken and copious irrigation of the pelvic and abdominal cavities should be performed to minimize the risk of retained
  tissue.
• Further investigations of a means to identify LMS preoperatively should be supported. Likewise, investigation into the biology of LMS should be funded to better understand the propensity of tissue fragments or cells to implant and grow. With that knowledge, minimally invasive procedures could be avoided for women with LMS and women choosing minimally invasive surgery could be reassured that they do not have LMS.

Respecting women who suffer from LMS, we conclude that the FDA directive was based on a misleading analysis. Consequently, more accurate estimates regarding the prevalence of LMS among women having surgery for fibroids should be issued. Women have a right to self determination. Modification of the FDA’s current restrictive guidance regarding power morcellation would empower each woman to consider the pertinent issues and have the freedom to undertake shared decision making with her surgeon in order to select the procedure that is most appropriate for her.

References
1. Siedhoff MT, Wheeler SB, Rutstein SE, et al. Laparoscopic hysterectomy with morcellation vs abdominal hysterectomy for presumed fibroid tumors in premenopausal women: a decision analysis. Am J Obstet Gynecol. 2015;212(5):591.e1–e8.
2. Harris JA, Swenson CW, Uppal S, et al. Practice patterns and postoperative complications before and after Food and Drug Administration Safety Communication on power morcellation [published online ahead of print August 24, 2015]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2015.08.047.

“CAN WE REDUCE THE USE OF ABDOMINAL HYSTERECTOMY AND INCREASE THE USE OF VAGINAL AND LAPAROSCOPIC APPROACHES?”
ROBERT L. BARBIERI, MD (EDITORIAL; NOVEMBER 2015)

Choose the best approach for the patient
I cannot decrease the number of abdominal hysterectomies I perform—all of them are indicated. 
Richard Hatch, MD
Augusta, Georgia

Supracervical hysterectomy: simplest is best
Supracervical hysterectomy (SCH) via a Pfannenstiel incision in women with a body mass index less than 25 kg/m² is a great procedure for uterine pathology. SCH addresses only the uterine pathology and preserves the cervix, is a sterile procedure, requires no ancillary equipment, should take less than 30 minutes, preserves the full length of the vagina, requires only an overnight hospitalization, and has a short learning curve.

Removal of the cervix in any hysterectomy is the procedure that results in bladder and ureter injury and infection from contamination. Patients should be driving and back to nonphysical jobs in less than 1 week. As medical care becomes a truly transparent market-based business, patients will opt for SCH over higher priced alternatives. Sometimes the simplest procedures are still the best.
Joe Walsh, MD
Philadelphia, Pennsylvania

Continue to teach abdominal hysterectomy
No one can disagree with the statistics of shorter recovery and less morbidity for laparoscopic and vaginal procedures. In fact, what separates a gynecologist from other surgeons is the ability to operate in and through the vagina. There is still a place for abdominal hysterectomy for benign disease in modern gynecology.

Most programs produce good laparoscopic surgeons but ill prepared abdominal and vaginal surgeons. No gynecologist should be operating in the pelvis unless he or she is comfortable going into the retroperitoneal space if necessary. Many of the total laparoscopic hysterectomies that are performed could be done vaginally without abdominal incisions.

Now we have a generation of gynecologic surgeons who believe a robotic hysterectomy (at great extra expense) offers the patient an advantage, despite longer anesthesia and procedure times. We know morbidity has a direct correlation to operating and anesthesia time. Although I am impressed with what the next generation can do through a laparoscope, I would hate to let them continue without the experience or the ability to do an open abdominal procedure.
Allan N. Boruszak, MD
Washington, North Carolina

Dr. Barbieri’s response
I appreciate the perspectives of Drs. Hatch, Walsh, and Boruszak on the important issue of improving hysterectomy outcomes. Dr. Hatch raises the important point that gynecologists routinely select the best surgical approach for the unique needs of their patients. Based on a given gynecologist’s panel of patients and their unique medical issues, it may be difficult to change the distribution of surgical approaches to hysterectomy. Dr. Walsh advocates for a “minimally invasive” abdominal SCH, which is a valid approach to improving the outcomes of the abdominal approach. Dr. Boruszak rightly highlights the importance of teaching gynecologists to access the retroperitoneum, paravesical, and pararectal spaces in order to improve patient outcomes.

“VAGINAL HYSTERECTOMY WITH BASIC INSTRUMENTATION”
BARBARA S. LEVY, MD (OCTOBER, 2015)

Appreciates the instrument review
Dr. Levy’s article on vaginal hysterectomy using basic instruments is really wonderful. The segment on uterine reduction strategies will be especially useful. I appreciate her preference to use the Ligasure vessel-sealing device over suturing pedicles. Before we take steps to debulk the uterus, it is always essential, and better, to ligate uterine vessels, as this minimizes blood loss and makes the surgical field clearer.
R. Sasirekha
Puducherry, India

Skill should be rewarded
When I trained, vaginal hysterectomy was reserved for prolapse. After joining the Army, my eyes were opened by physicians who could morcellate a 16-week uterus or perform a 20-minute vaginal hysterectomy on a nulliparous woman for sterilization (which, of course, is controversial).

Once in private practice, incorporating these new skills into my own techniques was challenging and rewarding. Imagine my disappointment when I found out that reimbursement was a disincentive. It is easy to be altruistic, but one has to consider the incentives, too. Skill should be rewarded.
Mark B. Vizer, MD
Lansdale, Pennsylvania

A long-time proponent of vaginal hysterectomy
I appreciate the articles by Drs. Levy and Gebhart on vaginal surgical techniques. I have long been a proponent of vaginal hysterectomy as the preferred route for removal of the uterus (and tubes and ovaries, if indicated). I do most of my hysterectomies vaginally, with salpingectomies and oophorectomies if indicated. As an older surgeon, I now refer patients with uteri larger than 16 weeks, endometriosis, or suspected cancer.
Doug Tolley, MD
Yuba City, California

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

AN OPEN LETTER TO THE FDA ON MORCELLATION FOR PRESUMED UTERINE FIBROIDS
On December 8, 2015, 46 minimally invasive surgeons, gynecologic oncologists, and other experts spoke out in unison when they sent an open letter to the US Food and Drug Administration (FDA). They called into question the FDA’s estimate of the likelihood of occult leiomyosarcoma (LMS) and recommended continued use of power morcellation in appropriate cases.

An excerpt from this letter is published here. To read the letter in its entirety and the names of the signees, click here. 

Letter excerpt:

If abdominal hysterectomy is recommended to women with fibroids, will women be better off?
By focusing exclusively on the risk of LMS, the FDA failed to take into account other risks associated with surgery. Laparoscopic surgery uses small incisions, is performed as an outpatient procedure (or overnight stay), has a faster recovery (2 weeks vs 4–6 weeks for open surgery), and is associated with lower mortality and fewer complications. These benefits of minimally invasive surgery are now well established in gynecologic and general surgery.

Using published best-evidence data, a recent decision analysis¹ showed that, comparing 100,000 women undergoing laparoscopic hysterectomy with 100,000 undergoing open hysterectomy, the group undergoing laparoscopic surgery would experience 20 fewer perioperative deaths, 150 fewer pulmonary or venous embolus, and 4,800 fewer wound infections. Importantly, women having open surgery would have 8,000 fewer quality-of-life years.

A recently published study² found that, in the 8 months following the FDA safety communication, utilization of laparoscopic hysterectomies decreased by 4.1% (P = .005), and abdominal and vaginal hysterectomies increased by 1.7% (P = .112) and 2.4% (P = .012), respectively. Major surgical complications (not including blood transfusions) increased from 2.2% to 2.8% (P = .015), and the rate of hospital readmission within 30 days also increased from 3.4% to 4.2% (P = .025). These observations merit consideration as women weigh the pros and cons of minimally invasive surgery with morcellation versus open surgery.

Clinical recommendations
Recent attention to surgical options for women with uterine leiomyomas and the risk of an occult LMS are positive developments in that the gynecologic community is reexamining relevant issues. We respectfully suggest that the following clinical recommendations be considered:

• The risk of LMS is higher in older postmenopausal women; greater caution should be exercised prior to recommending morcellation procedures for these women.
• Preoperative consideration of LMS is important. Women aged 35 years and older with irregular uterine bleeding and presumed fibroids should have an endometrial biopsy, which occasionally may detect LMS prior to surgery. Women should have normal results of cervical cancer screening.
• Ultrasound or MRI findings of a large irregular vascular mass, often with irregular anechoic (cystic) areas reflecting necrosis, may cause suspicion of LMS.
• Women wishing minimally invasive procedures with morcellation, including scalpel morcellation via the vagina or mini-laparotomy, or power morcellation using laparoscopic guidance, should understand the potential risk of decreased survival should LMS be present. Open procedures should be offered to all women who are considering minimally invasive procedures for “fibroids.”
• Following morcellation, careful inspection for tissue fragments should be undertaken and copious irrigation of the pelvic and abdominal cavities should be performed to minimize the risk of retained
  tissue.
• Further investigations of a means to identify LMS preoperatively should be supported. Likewise, investigation into the biology of LMS should be funded to better understand the propensity of tissue fragments or cells to implant and grow. With that knowledge, minimally invasive procedures could be avoided for women with LMS and women choosing minimally invasive surgery could be reassured that they do not have LMS.

Respecting women who suffer from LMS, we conclude that the FDA directive was based on a misleading analysis. Consequently, more accurate estimates regarding the prevalence of LMS among women having surgery for fibroids should be issued. Women have a right to self determination. Modification of the FDA’s current restrictive guidance regarding power morcellation would empower each woman to consider the pertinent issues and have the freedom to undertake shared decision making with her surgeon in order to select the procedure that is most appropriate for her.

References
1. Siedhoff MT, Wheeler SB, Rutstein SE, et al. Laparoscopic hysterectomy with morcellation vs abdominal hysterectomy for presumed fibroid tumors in premenopausal women: a decision analysis. Am J Obstet Gynecol. 2015;212(5):591.e1–e8.
2. Harris JA, Swenson CW, Uppal S, et al. Practice patterns and postoperative complications before and after Food and Drug Administration Safety Communication on power morcellation [published online ahead of print August 24, 2015]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2015.08.047.

“CAN WE REDUCE THE USE OF ABDOMINAL HYSTERECTOMY AND INCREASE THE USE OF VAGINAL AND LAPAROSCOPIC APPROACHES?”
ROBERT L. BARBIERI, MD (EDITORIAL; NOVEMBER 2015)

Choose the best approach for the patient
I cannot decrease the number of abdominal hysterectomies I perform—all of them are indicated. 
Richard Hatch, MD
Augusta, Georgia

Supracervical hysterectomy: simplest is best
Supracervical hysterectomy (SCH) via a Pfannenstiel incision in women with a body mass index less than 25 kg/m² is a great procedure for uterine pathology. SCH addresses only the uterine pathology and preserves the cervix, is a sterile procedure, requires no ancillary equipment, should take less than 30 minutes, preserves the full length of the vagina, requires only an overnight hospitalization, and has a short learning curve.

Removal of the cervix in any hysterectomy is the procedure that results in bladder and ureter injury and infection from contamination. Patients should be driving and back to nonphysical jobs in less than 1 week. As medical care becomes a truly transparent market-based business, patients will opt for SCH over higher priced alternatives. Sometimes the simplest procedures are still the best.
Joe Walsh, MD
Philadelphia, Pennsylvania

Continue to teach abdominal hysterectomy
No one can disagree with the statistics of shorter recovery and less morbidity for laparoscopic and vaginal procedures. In fact, what separates a gynecologist from other surgeons is the ability to operate in and through the vagina. There is still a place for abdominal hysterectomy for benign disease in modern gynecology.

Most programs produce good laparoscopic surgeons but ill prepared abdominal and vaginal surgeons. No gynecologist should be operating in the pelvis unless he or she is comfortable going into the retroperitoneal space if necessary. Many of the total laparoscopic hysterectomies that are performed could be done vaginally without abdominal incisions.

Now we have a generation of gynecologic surgeons who believe a robotic hysterectomy (at great extra expense) offers the patient an advantage, despite longer anesthesia and procedure times. We know morbidity has a direct correlation to operating and anesthesia time. Although I am impressed with what the next generation can do through a laparoscope, I would hate to let them continue without the experience or the ability to do an open abdominal procedure.
Allan N. Boruszak, MD
Washington, North Carolina

Dr. Barbieri’s response
I appreciate the perspectives of Drs. Hatch, Walsh, and Boruszak on the important issue of improving hysterectomy outcomes. Dr. Hatch raises the important point that gynecologists routinely select the best surgical approach for the unique needs of their patients. Based on a given gynecologist’s panel of patients and their unique medical issues, it may be difficult to change the distribution of surgical approaches to hysterectomy. Dr. Walsh advocates for a “minimally invasive” abdominal SCH, which is a valid approach to improving the outcomes of the abdominal approach. Dr. Boruszak rightly highlights the importance of teaching gynecologists to access the retroperitoneum, paravesical, and pararectal spaces in order to improve patient outcomes.

“VAGINAL HYSTERECTOMY WITH BASIC INSTRUMENTATION”
BARBARA S. LEVY, MD (OCTOBER, 2015)

Appreciates the instrument review
Dr. Levy’s article on vaginal hysterectomy using basic instruments is really wonderful. The segment on uterine reduction strategies will be especially useful. I appreciate her preference to use the Ligasure vessel-sealing device over suturing pedicles. Before we take steps to debulk the uterus, it is always essential, and better, to ligate uterine vessels, as this minimizes blood loss and makes the surgical field clearer.
R. Sasirekha
Puducherry, India

Skill should be rewarded
When I trained, vaginal hysterectomy was reserved for prolapse. After joining the Army, my eyes were opened by physicians who could morcellate a 16-week uterus or perform a 20-minute vaginal hysterectomy on a nulliparous woman for sterilization (which, of course, is controversial).

Once in private practice, incorporating these new skills into my own techniques was challenging and rewarding. Imagine my disappointment when I found out that reimbursement was a disincentive. It is easy to be altruistic, but one has to consider the incentives, too. Skill should be rewarded.
Mark B. Vizer, MD
Lansdale, Pennsylvania

A long-time proponent of vaginal hysterectomy
I appreciate the articles by Drs. Levy and Gebhart on vaginal surgical techniques. I have long been a proponent of vaginal hysterectomy as the preferred route for removal of the uterus (and tubes and ovaries, if indicated). I do most of my hysterectomies vaginally, with salpingectomies and oophorectomies if indicated. As an older surgeon, I now refer patients with uteri larger than 16 weeks, endometriosis, or suspected cancer.
Doug Tolley, MD
Yuba City, California

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

AN OPEN LETTER TO THE FDA ON MORCELLATION FOR PRESUMED UTERINE FIBROIDS
On December 8, 2015, 46 minimally invasive surgeons, gynecologic oncologists, and other experts spoke out in unison when they sent an open letter to the US Food and Drug Administration (FDA). They called into question the FDA’s estimate of the likelihood of occult leiomyosarcoma (LMS) and recommended continued use of power morcellation in appropriate cases.

An excerpt from this letter is published here. To read the letter in its entirety and the names of the signees, click here. 

Letter excerpt:

If abdominal hysterectomy is recommended to women with fibroids, will women be better off?
By focusing exclusively on the risk of LMS, the FDA failed to take into account other risks associated with surgery. Laparoscopic surgery uses small incisions, is performed as an outpatient procedure (or overnight stay), has a faster recovery (2 weeks vs 4–6 weeks for open surgery), and is associated with lower mortality and fewer complications. These benefits of minimally invasive surgery are now well established in gynecologic and general surgery.

Using published best-evidence data, a recent decision analysis¹ showed that, comparing 100,000 women undergoing laparoscopic hysterectomy with 100,000 undergoing open hysterectomy, the group undergoing laparoscopic surgery would experience 20 fewer perioperative deaths, 150 fewer pulmonary or venous embolus, and 4,800 fewer wound infections. Importantly, women having open surgery would have 8,000 fewer quality-of-life years.

A recently published study² found that, in the 8 months following the FDA safety communication, utilization of laparoscopic hysterectomies decreased by 4.1% (P = .005), and abdominal and vaginal hysterectomies increased by 1.7% (P = .112) and 2.4% (P = .012), respectively. Major surgical complications (not including blood transfusions) increased from 2.2% to 2.8% (P = .015), and the rate of hospital readmission within 30 days also increased from 3.4% to 4.2% (P = .025). These observations merit consideration as women weigh the pros and cons of minimally invasive surgery with morcellation versus open surgery.

Clinical recommendations
Recent attention to surgical options for women with uterine leiomyomas and the risk of an occult LMS are positive developments in that the gynecologic community is reexamining relevant issues. We respectfully suggest that the following clinical recommendations be considered:

• The risk of LMS is higher in older postmenopausal women; greater caution should be exercised prior to recommending morcellation procedures for these women.
• Preoperative consideration of LMS is important. Women aged 35 years and older with irregular uterine bleeding and presumed fibroids should have an endometrial biopsy, which occasionally may detect LMS prior to surgery. Women should have normal results of cervical cancer screening.
• Ultrasound or MRI findings of a large irregular vascular mass, often with irregular anechoic (cystic) areas reflecting necrosis, may cause suspicion of LMS.
• Women wishing minimally invasive procedures with morcellation, including scalpel morcellation via the vagina or mini-laparotomy, or power morcellation using laparoscopic guidance, should understand the potential risk of decreased survival should LMS be present. Open procedures should be offered to all women who are considering minimally invasive procedures for “fibroids.”
• Following morcellation, careful inspection for tissue fragments should be undertaken and copious irrigation of the pelvic and abdominal cavities should be performed to minimize the risk of retained
  tissue.
• Further investigations of a means to identify LMS preoperatively should be supported. Likewise, investigation into the biology of LMS should be funded to better understand the propensity of tissue fragments or cells to implant and grow. With that knowledge, minimally invasive procedures could be avoided for women with LMS and women choosing minimally invasive surgery could be reassured that they do not have LMS.

Respecting women who suffer from LMS, we conclude that the FDA directive was based on a misleading analysis. Consequently, more accurate estimates regarding the prevalence of LMS among women having surgery for fibroids should be issued. Women have a right to self determination. Modification of the FDA’s current restrictive guidance regarding power morcellation would empower each woman to consider the pertinent issues and have the freedom to undertake shared decision making with her surgeon in order to select the procedure that is most appropriate for her.

References
1. Siedhoff MT, Wheeler SB, Rutstein SE, et al. Laparoscopic hysterectomy with morcellation vs abdominal hysterectomy for presumed fibroid tumors in premenopausal women: a decision analysis. Am J Obstet Gynecol. 2015;212(5):591.e1–e8.
2. Harris JA, Swenson CW, Uppal S, et al. Practice patterns and postoperative complications before and after Food and Drug Administration Safety Communication on power morcellation [published online ahead of print August 24, 2015]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2015.08.047.

“CAN WE REDUCE THE USE OF ABDOMINAL HYSTERECTOMY AND INCREASE THE USE OF VAGINAL AND LAPAROSCOPIC APPROACHES?”
ROBERT L. BARBIERI, MD (EDITORIAL; NOVEMBER 2015)

Choose the best approach for the patient
I cannot decrease the number of abdominal hysterectomies I perform—all of them are indicated. 
Richard Hatch, MD
Augusta, Georgia

Supracervical hysterectomy: simplest is best
Supracervical hysterectomy (SCH) via a Pfannenstiel incision in women with a body mass index less than 25 kg/m² is a great procedure for uterine pathology. SCH addresses only the uterine pathology and preserves the cervix, is a sterile procedure, requires no ancillary equipment, should take less than 30 minutes, preserves the full length of the vagina, requires only an overnight hospitalization, and has a short learning curve.

Removal of the cervix in any hysterectomy is the procedure that results in bladder and ureter injury and infection from contamination. Patients should be driving and back to nonphysical jobs in less than 1 week. As medical care becomes a truly transparent market-based business, patients will opt for SCH over higher priced alternatives. Sometimes the simplest procedures are still the best.
Joe Walsh, MD
Philadelphia, Pennsylvania

Continue to teach abdominal hysterectomy
No one can disagree with the statistics of shorter recovery and less morbidity for laparoscopic and vaginal procedures. In fact, what separates a gynecologist from other surgeons is the ability to operate in and through the vagina. There is still a place for abdominal hysterectomy for benign disease in modern gynecology.

Most programs produce good laparoscopic surgeons but ill prepared abdominal and vaginal surgeons. No gynecologist should be operating in the pelvis unless he or she is comfortable going into the retroperitoneal space if necessary. Many of the total laparoscopic hysterectomies that are performed could be done vaginally without abdominal incisions.

Now we have a generation of gynecologic surgeons who believe a robotic hysterectomy (at great extra expense) offers the patient an advantage, despite longer anesthesia and procedure times. We know morbidity has a direct correlation to operating and anesthesia time. Although I am impressed with what the next generation can do through a laparoscope, I would hate to let them continue without the experience or the ability to do an open abdominal procedure.
Allan N. Boruszak, MD
Washington, North Carolina

Dr. Barbieri’s response
I appreciate the perspectives of Drs. Hatch, Walsh, and Boruszak on the important issue of improving hysterectomy outcomes. Dr. Hatch raises the important point that gynecologists routinely select the best surgical approach for the unique needs of their patients. Based on a given gynecologist’s panel of patients and their unique medical issues, it may be difficult to change the distribution of surgical approaches to hysterectomy. Dr. Walsh advocates for a “minimally invasive” abdominal SCH, which is a valid approach to improving the outcomes of the abdominal approach. Dr. Boruszak rightly highlights the importance of teaching gynecologists to access the retroperitoneum, paravesical, and pararectal spaces in order to improve patient outcomes.

“VAGINAL HYSTERECTOMY WITH BASIC INSTRUMENTATION”
BARBARA S. LEVY, MD (OCTOBER, 2015)

Appreciates the instrument review
Dr. Levy’s article on vaginal hysterectomy using basic instruments is really wonderful. The segment on uterine reduction strategies will be especially useful. I appreciate her preference to use the Ligasure vessel-sealing device over suturing pedicles. Before we take steps to debulk the uterus, it is always essential, and better, to ligate uterine vessels, as this minimizes blood loss and makes the surgical field clearer.
R. Sasirekha
Puducherry, India

Skill should be rewarded
When I trained, vaginal hysterectomy was reserved for prolapse. After joining the Army, my eyes were opened by physicians who could morcellate a 16-week uterus or perform a 20-minute vaginal hysterectomy on a nulliparous woman for sterilization (which, of course, is controversial).

Once in private practice, incorporating these new skills into my own techniques was challenging and rewarding. Imagine my disappointment when I found out that reimbursement was a disincentive. It is easy to be altruistic, but one has to consider the incentives, too. Skill should be rewarded.
Mark B. Vizer, MD
Lansdale, Pennsylvania

A long-time proponent of vaginal hysterectomy
I appreciate the articles by Drs. Levy and Gebhart on vaginal surgical techniques. I have long been a proponent of vaginal hysterectomy as the preferred route for removal of the uterus (and tubes and ovaries, if indicated). I do most of my hysterectomies vaginally, with salpingectomies and oophorectomies if indicated. As an older surgeon, I now refer patients with uteri larger than 16 weeks, endometriosis, or suspected cancer.
Doug Tolley, MD
Yuba City, California

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

In November 2014, the FDA ruled that power morcellation was contraindicated in "the majority of women" having surgery for uterine fibroids due to the potential risk of spreading occult uterine sarcoma.¹ Although problems with this ruling were immediately apparent, the passage of time has allowed for more clarity on the related medical issues.

Prevalence of leiomyosarcoma among women having surgery for presumed uterine fibroids
The prevalence of occult leiomyosarcoma among women with fibroids is critical for every patient. All medical procedures have potential risk and the patient's understanding of risk is the foundation of medical decision making.

The FDA estimated that for every 458 women having surgery for fibroids, one woman would be found to have an occult leiomyosarcoma (LMS). We challenge this calculation. To estimate this risk, the FDA searched medical databases using the terms “uterine cancer” AND “hysterectomy or myomectomy.” Because “uterine cancer” was required, studies where cancer was not found or discussed were not identified. Nine studies, all but one of which were retrospective, were analyzed including a non–peer-reviewed Letter to the Editor and an abstract from an unpublished study.^2,3

Additionally, 3 leiomyosarcoma cases identified by the FDA do not meet current pathologic criteria for cancer and would now be classified as benign "atypical" leiomyomas. If atypical leiomyomas and non–peer-reviewed data are excluded, the FDA identified 8 cases of LMS among 12,402 women having surgery for presumed leiomyomas, a prevalence of 1 in 1,550 (0.064%).

Pritts and colleagues⁴ recently published a more rigorous meta-analysis of 133 studies and determined that the prevalence of LMS among women having surgery for presumed fibroids was 1 in 1,960, or 0.051%. All peer-reviewed reports in which surgery was performed for presumed fibroids were analyzed, including reports where cancer was not found. Inclusion criteria required that histopathology results be explicitly provided and available for interpretation. Among the 26 randomized controlled trials analyzed, 1,582 women had surgery for fibroids and none were found to have LMS.

Bojahr and colleagues⁵ recently published a large population-based prospective registry study and reported 2 occult LMS among 8,720 women having surgery for fibroids (0.023%).

In summary: The re-analyzed FDA dataset yields a prevalence of 1 in 1,550 (0.064%); the Pritts study reports a prevalence of 1 in 1,960 (0.051%), with the RCTs having a prevalence of 0; and the Bojahr study reports a prevalence of 2 of 8,720 (0.023%). We acknowledge that with rare events statistical analysis may be uncertain and confidence intervals may be wide. However, these numbers do not support the FDA's estimated prevalence of LMS among women having surgery for presumed fibroids and those at risk for morcellation of an LMS.

Prognosis for women with morcellated LMS
Women with LMS, removed intact without morcellation, have a poor prognosis. Based on SEER data, the 5-year survival of stage I and II LMS is only 61%.⁶ Whether morcellation influences the prognosis of women with LMS is not known, and the biology of this tumor has not been well studied. Distant metastases occur early in the disease process, primarily hematogenous dissemination. Four frequently quoted published studies examine survival following power morcellation. Surprisingly, virtually none of the women in these studies had power morcellation. Furthermore, the data presented in these reports are poorly analyzed and patient numbers are very small.

Park and colleagues⁷ reported only one of the 25 morcellated cases had laparoscopic surgery with power morcellation. Eighteen women had a laparoscopically-assisted vaginal hysterectomy with scalpel morcellation performed through the vagina, one had a vaginal hysterectomy with scalpel-morcellation, and 5 had mini-laparotomy with scalpel morcellation through small lower abdominal incisions. Seventeen of the 25 patients plotted in the published survival curve were referred to the hospital after initial diagnosis or the discovery of a recurrence at another institution. Since the number of nonreferred women with less aggressive disease or without recurrence is not known, it is not possible to determine differences in survival between patients with and without morcellation.

In a study by Perri and colleagues,⁸ none of the patients had power morcellation: 4 women had abdominal myomectomy; 4 had hysteroscopic myomectomy with tissue confined within the uterine cavity; 2 had laparoscopic hysterectomy with scalpel morcellation; 4 had supracervical abdominal hysterectomy with cut-through at the cervix; and 2 had abdominal hysterectomy with injury to the uterus with a sharp instrument.

When comparing the outcomes for women with morcellated and nonmorcellated LMS, Morice and colleagues⁹ found no difference in recurrence rates or overall and disease-free survival at 6 months.

In the only study to compare use of power with scalpel morcellation in women with LMS, Oduyebo and colleagues¹⁰ found no difference in outcomes for the 10 women with power morcellation and 5 with scalpel morcellation followed for a median of 27 months (range, 2–93 months). Notably, a life table analysis of the above studies showed no difference in survival between morcellation methods.¹¹

Of note, laparoscopic-aided morcellation allows the surgeon to inspect the pelvic and abdominal cavities and irrigate and remove tissue fragments under visual control. In contrast, the surgeon cannot visually inspect the peritoneal cavity during vaginal or mini-laparotomy procedures. Morcellation within containment bags has recently been utilized in an attempt to avoid spread of tissue. This method has not yet been proven effective or safe, and there is concern that bags may make morcellation more cumbersome and less safe.

What the FDA restrictions mean for women
The FDA communication states, "the FDA is warning against the use of laparoscopic power morcellators in the majority of women undergoing hysterectomy or myomectomy for uterine fibroids."¹ This statement is not consistent with current evidence.

Moreover, a severe restriction of morcellation, including vaginal and mini-laparotomy morcellation, would limit women with symptomatic leiomyomas to one option: total abdominal hysterectomy. For women with fibroids larger than a 10-week pregnancy size, which most often require either scalpel or power morcellation in order to remove tissue, a ban on morcellation would eliminate the following procedures:

• vaginal hysterectomy (scalpel morcellation)
• mini-laparotomy hysterectomy (scalpel morcellation)
• laparoscopic hysterectomy (scalpel morcellation)
• laparoscopic supracervical hysterectomy (cervix cut-through)
• open supracervical hysterectomy (cervix cut-through)
• laparoscopic myomectomy (power morcellation)
• mini-laparotomy myomectomy (scalpel morcellation)
• hysteroscopic myomectomy (intrauterine morcellation)
• uterine artery embolization (no specimen and will delay diagnosis)
• high-intensity focused ultrasound (no specimen and will delay diagnosis)

If abdominal hysterectomy is recommended to women with fibroids, will women be better off?
By focusing exclusively on the risk of LMS, the FDA failed to take into account other risks associated with surgery. Laparoscopic surgery uses small incisions, is performed as an outpatient procedure (or overnight stay), has a faster recovery (2 weeks vs 4–6 weeks for open surgery), and is associated with lower mortality and fewer complications. These benefits of minimally invasive surgery are now well established in gynecologic and general surgery.

Using published best-evidence data, a recent decision analysis¹² showed that, comparing 100,000 women undergoing laparoscopic hysterectomy with 100,000 undergoing open hysterectomy, the group undergoing laparoscopic surgery would experience 20 fewer perioperative deaths, 150 fewer pulmonary or venous embolus, and 4,800 fewer wound infections. Importantly, women having open surgery would have 8,000 fewer quality-of-life years.

A recently published study¹³ found that, in the 8 months following the FDA safety communication, utilization of laparoscopic hysterectomies decreased by 4.1% (P = .005), and abdominal and vaginal hysterectomies increased by 1.7% (P = .112) and 2.4% (P = .012), respectively. Major surgical complications (not including blood transfusions) increased from 2.2% to 2.8% (P = .015), and the rate of hospital readmission within 30 days also increased from 3.4% to 4.2% (P = .025). These observations merit consideration as women weigh the pros and cons of minimally invasive surgery with morcellation versus open surgery. These observations merit consideration as women weigh the pros and cons of minimally invasive surgery with possible morcellation versus open surgery.

Clinical recommendations
Recent attention to surgical options for women with uterine leiomyomas and the risk of an occult leiomyosarcoma are positive developments in that the gynecologic community is re-examining relevant issues. We respectfully suggest that the following clinical recommendations be considered:

• The risk of LMS is higher in older postmenopausal women; greater caution should be exercised prior to recommending morcellation procedures for these women.
• Preoperative consideration of LMS is important. Women aged 35 years and older with irregular uterine bleeding and presumed fibroids should have an endometrial biopsy, which occasionally may detect LMS prior to surgery. Women should have normal results of cervical cancer screening.
• Ultrasound or MRI findings of a large irregular vascular mass, often with irregular anechoic (cystic) areas reflecting necrosis, may cause suspicion of LMS.
• Women wishing minimally invasive procedures with morcellation, including scalpel morcellation via the vagina or mini-laparotomy, or power morcellation using laparoscopic guidance, should understand the potential risk of decreased survival should LMS be present. Open procedures should be offered to all women who are considering minimally invasive procedures for "fibroids."
• Following morcellation, careful inspection for tissue fragments should be undertaken and copious irrigation of the pelvic and abdominal cavities should be performed to minimize the risk of retained tissue.
• Further investigations of a means to identify LMS preoperatively should be supported. Likewise, investigation into the biology of LMS should be funded to better understand the propensity of tissue fragments or cells to implant and grow. With that knowledge, minimally invasive procedures could be avoided for women with LMS and women choosing minimally invasive surgery could be reassured that they do not have LMS.

Respecting women who suffer from leiomyosarcoma, we conclude that the FDA directive was based on a misleading analysis. Consequently, more accurate estimates regarding the prevalence of LMS among women having surgery for fibroids should be issued. Women have a right to self determination. Modification of the FDA's current restrictive guidance regarding power morcellation would empower each woman to consider the pertinent issues and have the freedom to undertake shared decision making with her surgeon in order to select the procedure that is most appropriate for her.

William Parker, MD
Clinical Professor, University of California Los Angeles (UCLA) School of Medicine, Director, Minimally Invasive Gynecologic Surgery, Santa Monica-UCLA Medical Center, Santa Monica, California

Jonathan S. Berek, MD, MMS
Laurie Kraus Lacob Professor and Director, Stanford Women's Cancer Center, Director, Stanford Health Care Communication Program, Chair, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California

Elizabeth Pritts, MD
Wisconsin Fertility Institute, Middleton, Wisconsin

David Olive, MD
Wisconsin Fertility Institute, Middleton, Wisconsin

Andrew M. Kaunitz, MD
University of Florida Research Foundation Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville; Director, Menopause and Gynecologic Ultrasound Services, UF Women’s Health Specialists at Emerson, Jacksonville, Florida.

Eva Chalas, MD
Chief, Division of Gynecologic Oncology, Director, Clinical Cancer Services, Vice-Chair, Department of Obstetrics and Gynecology, Winthrop-University Hospital, Mineola, New York

Daniel Clarke-Pearson, MD
Professor and Chair, Clinical Research, Gynecologic Oncology Program, University of North Carolina at Chapel Hill

Barbara Goff, MD
Professor, Obstetrics and Gynecology, Director, Division of Gynecologic Oncology, University of Washington, Seattle, Washington

Robert E. Bristow, MD, MBA
Professor and Chair, Department of Obstetrics and Gynecology, University of California Irvine School of Medicine, Orange, California

Hugh S. Taylor, MD
Anita O'Keeffe Young Professor and Chair, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicin; Chief of Obstetrics and Gynecology, Yale-New Haven Hospital, New Haven, Connecticut

Robin Farias-Eisner, MD
Chief, Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California Los Angeles

Amanda Nickles Fader, MD
Director, Kelly Gynecologic Oncology Service, Associate Professor of Gynecology and Obstetrics, Director, FJ Montz Fellowship in Gynecologic Oncology, Johns Hopkins Medicine, Baltimore, Maryland

G. Larry Maxwell, MD, COL (ret) US Army
Chairman, Department of Obstetrics and Gynecology, Inova Fairfax Hospital, Falls Church, Virginia; Co-Investigator and Deputy Director of Science, Department of Defense Gynecologic Cancer Translational Research Center of Excellence, Bethesda, Maryland; Professor of Virginia Commonwealth School of Medicine, Richmond, Virginia; and Executive Director of Globeathon to End Women’s Cancer

Scott C. Goodwin, MD
Hasso Brothers Professor and Chairman, Radiological Sciences, University of California Irvine Medical Center, Orange, California

Susan Love, MD, MBA
Dr. Susan Love Research Foundation, Encino, California

William E. Gibbons, MD
Professor and Director, Division of Reproductive Medicine, Director of Fellowship Training, Department of Obstetrics and Gynecology, Baylor College of Medicine; Chief of Reproductive Medicine at the Pavilion For Women at Texas Children’s Hospital, Houston, Texas

Leland J. Foshag, MD
Surgical Oncology, Melanoma and Sarcoma, John Wayne Cancer Institute, Santa Monica, California

Phyllis C. Leppert, MD, PhD
Emerita Professor of Obstetrics and Gynecology, Duke University School of Medicine; President of The Campion Fund, Phyllis and Mark Leppert Foundation for Fertility Research, Durham, North Carolina

Judy Norsigian
Co-founder of Our Bodies, Ourselves, Boston, Massachusetts

Charles W. Nager, MD
Professor and Chairman, Department of Reproductive Medicine, University of California San Diego Health System

Timothy Robert B. Johnson, MD
Arthur F. Thurnau Professor and Chair, Department of Obstetrics and Gynecology, Professor of Women’s Studies, and Research Professor in the Center for Human Growth and Development, University of Michigan, Ann Arbor, Michigan

David S. Guzick, MD, PhD
Senior Vice President of Health Affairs, President of UF Health, University of Florida, Gainesville, Florida

Sawsan As-Sanie, MD, MPH
Assistant Professor and Director, Minimally Invasive Gynecologic Surgery, Fellowship Director of Endometriosis Center, University of Michigan, Ann Arbor, Michigan

Richard J. Paulson, MD
Alia Tutor Chair in Reproductive Medicine, Professor and Vice-Chair, Department of Obstetrics and Gynecology, Chief, Division of Reproductive Endocrinology and Infertility, Keck School of Medicine, University of Southern California, Los Angeles, California

Cindy Farquhar
Professor of Obstetrics and Gynaecology and National Women's Health, University of Auckland, New Zealand

Linda Bradley, MD
Vice Chair of Obstetrics, Gynecology, and Women’s Health Institute, Director of the Fibroid and Menstrual Disorders Center, Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, Ohio.

Stacey A. Scheib, MD
Assistant Professor and Director, Hopkins Multidisciplinary Fibroid Center, Director of Minimally Invasive Gynecologic Surgery, Johns Hopkins Hospital, Baltimore, Maryland

Anton J. Bilchik, MD, PhD
Professor of Surgery, Chief of Medicine at John Wayne Cancer Institute, Santa Monica, California

Laurel W. Rice, MD
Chair, Department of Obstetrics and Gynecology, Professor, Division of Gynecology Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin

Carla Dionne
Founder of National Uterine Fibroid Foundation, Colorado Springs, Colorado

Alison Jacoby, MD
Director, University of California-San Francisco Comprehensive Fibroid Center, Interim Chief, Division of Gynecology, University of California San Francisco

Charles Ascher-Walsh, MD
Director of Gynecology, Urogynecology, and Minimally Invasive Surgery, Mt. Sinai School of Medicine, New York, New York

Sarah J. Kilpatrick, MD, PhD
Chair of Department of Obstetrics and Gynecology, Associate Dean of Faculty Development, Helping Hand of Los Angeles Chair in Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California

G. David Adamson, MD
Clinical Professor, Stanford University School of Medicine, Stanford, California; Past President of the American Society for Reproductive Medicine

Matthew Siedhoff, MD, MSCR
Assistant Professor and Division Director, Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill

Robert Israel, MD
Professor, Department of Obstetrics and Gynecology, Chair, Quality Improvement, Director, Women's Health Clinics and Referrals, LAC+USC Medical Center, Los Angeles, California

Marie Fidela Paraiso, MD
Head, Female Pelvic Medicine & Reconstructive Surgery, Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, Ohio

Michael M. Frumovitz, MD, MPH
Fellowship Program Director, Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas

John R. Lurain, MD
Marcia Stenn Professor of Gynecologic Oncology, Program Director, Fellowship in Gynecologic Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois

Ayman Al-Hendy, MD, PhD
Georgia Regents University Director of Interdisciplinary Translational Research; Medical College of Georgia Assistant Dean for Global Translational Research; Professor and Director, Division of Translational Research, Department of Obstetrics and Gynecology, Georgia Regents Health, Augusta, Georgia

Guy I. Benrubi, MD
Senior Associate Dean for Faculty Affairs, Robert J. Thompson Professor and Chair of Department of Obstetrics and Gynecology, University of Florida College of Medicine – Jacksonville

Steven S. Raman, MD
Professor, Radiology, Urology, and Surgery, Co-director, Fibroid Treatment Program, David Geffen School of Medicine at University of California Los Angeles

Rosanne M. Kho, MD
Associate Professor and Head, Section of Urogynecology and Female Pelvic Medicine & Reconstructive Surgery; Co-Director of Minimally Invasive Gynecologic Surgery Fellowship Program, Columbia University Medical Center, New York, New York

Ted L. Anderson, MD, PhD
Betty and Lonnie S. Burnett Professor and Chair, Obstetrics and Gynecology, Division Director of Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee

R. Kevin Reynolds, MD
The George W. Morley Professor and Chief, Division of Gynecologic Oncology, University of Michigan Health System, Ann Arbor, Michigan

John DeLancey, MD
Norman F. Miller Professor of Obstetrics & Gynecology, University of Michigan Health System, Ann Arbor, Michigan

In November 2014, the FDA ruled that power morcellation was contraindicated in "the majority of women" having surgery for uterine fibroids due to the potential risk of spreading occult uterine sarcoma.¹ Although problems with this ruling were immediately apparent, the passage of time has allowed for more clarity on the related medical issues.

Prevalence of leiomyosarcoma among women having surgery for presumed uterine fibroids
The prevalence of occult leiomyosarcoma among women with fibroids is critical for every patient. All medical procedures have potential risk and the patient's understanding of risk is the foundation of medical decision making.

The FDA estimated that for every 458 women having surgery for fibroids, one woman would be found to have an occult leiomyosarcoma (LMS). We challenge this calculation. To estimate this risk, the FDA searched medical databases using the terms “uterine cancer” AND “hysterectomy or myomectomy.” Because “uterine cancer” was required, studies where cancer was not found or discussed were not identified. Nine studies, all but one of which were retrospective, were analyzed including a non–peer-reviewed Letter to the Editor and an abstract from an unpublished study.^2,3

Additionally, 3 leiomyosarcoma cases identified by the FDA do not meet current pathologic criteria for cancer and would now be classified as benign "atypical" leiomyomas. If atypical leiomyomas and non–peer-reviewed data are excluded, the FDA identified 8 cases of LMS among 12,402 women having surgery for presumed leiomyomas, a prevalence of 1 in 1,550 (0.064%).

Pritts and colleagues⁴ recently published a more rigorous meta-analysis of 133 studies and determined that the prevalence of LMS among women having surgery for presumed fibroids was 1 in 1,960, or 0.051%. All peer-reviewed reports in which surgery was performed for presumed fibroids were analyzed, including reports where cancer was not found. Inclusion criteria required that histopathology results be explicitly provided and available for interpretation. Among the 26 randomized controlled trials analyzed, 1,582 women had surgery for fibroids and none were found to have LMS.

Bojahr and colleagues⁵ recently published a large population-based prospective registry study and reported 2 occult LMS among 8,720 women having surgery for fibroids (0.023%).

In summary: The re-analyzed FDA dataset yields a prevalence of 1 in 1,550 (0.064%); the Pritts study reports a prevalence of 1 in 1,960 (0.051%), with the RCTs having a prevalence of 0; and the Bojahr study reports a prevalence of 2 of 8,720 (0.023%). We acknowledge that with rare events statistical analysis may be uncertain and confidence intervals may be wide. However, these numbers do not support the FDA's estimated prevalence of LMS among women having surgery for presumed fibroids and those at risk for morcellation of an LMS.

Prognosis for women with morcellated LMS
Women with LMS, removed intact without morcellation, have a poor prognosis. Based on SEER data, the 5-year survival of stage I and II LMS is only 61%.⁶ Whether morcellation influences the prognosis of women with LMS is not known, and the biology of this tumor has not been well studied. Distant metastases occur early in the disease process, primarily hematogenous dissemination. Four frequently quoted published studies examine survival following power morcellation. Surprisingly, virtually none of the women in these studies had power morcellation. Furthermore, the data presented in these reports are poorly analyzed and patient numbers are very small.

Park and colleagues⁷ reported only one of the 25 morcellated cases had laparoscopic surgery with power morcellation. Eighteen women had a laparoscopically-assisted vaginal hysterectomy with scalpel morcellation performed through the vagina, one had a vaginal hysterectomy with scalpel-morcellation, and 5 had mini-laparotomy with scalpel morcellation through small lower abdominal incisions. Seventeen of the 25 patients plotted in the published survival curve were referred to the hospital after initial diagnosis or the discovery of a recurrence at another institution. Since the number of nonreferred women with less aggressive disease or without recurrence is not known, it is not possible to determine differences in survival between patients with and without morcellation.

In a study by Perri and colleagues,⁸ none of the patients had power morcellation: 4 women had abdominal myomectomy; 4 had hysteroscopic myomectomy with tissue confined within the uterine cavity; 2 had laparoscopic hysterectomy with scalpel morcellation; 4 had supracervical abdominal hysterectomy with cut-through at the cervix; and 2 had abdominal hysterectomy with injury to the uterus with a sharp instrument.

When comparing the outcomes for women with morcellated and nonmorcellated LMS, Morice and colleagues⁹ found no difference in recurrence rates or overall and disease-free survival at 6 months.

In the only study to compare use of power with scalpel morcellation in women with LMS, Oduyebo and colleagues¹⁰ found no difference in outcomes for the 10 women with power morcellation and 5 with scalpel morcellation followed for a median of 27 months (range, 2–93 months). Notably, a life table analysis of the above studies showed no difference in survival between morcellation methods.¹¹

Of note, laparoscopic-aided morcellation allows the surgeon to inspect the pelvic and abdominal cavities and irrigate and remove tissue fragments under visual control. In contrast, the surgeon cannot visually inspect the peritoneal cavity during vaginal or mini-laparotomy procedures. Morcellation within containment bags has recently been utilized in an attempt to avoid spread of tissue. This method has not yet been proven effective or safe, and there is concern that bags may make morcellation more cumbersome and less safe.

What the FDA restrictions mean for women
The FDA communication states, "the FDA is warning against the use of laparoscopic power morcellators in the majority of women undergoing hysterectomy or myomectomy for uterine fibroids."¹ This statement is not consistent with current evidence.

Moreover, a severe restriction of morcellation, including vaginal and mini-laparotomy morcellation, would limit women with symptomatic leiomyomas to one option: total abdominal hysterectomy. For women with fibroids larger than a 10-week pregnancy size, which most often require either scalpel or power morcellation in order to remove tissue, a ban on morcellation would eliminate the following procedures:

• vaginal hysterectomy (scalpel morcellation)
• mini-laparotomy hysterectomy (scalpel morcellation)
• laparoscopic hysterectomy (scalpel morcellation)
• laparoscopic supracervical hysterectomy (cervix cut-through)
• open supracervical hysterectomy (cervix cut-through)
• laparoscopic myomectomy (power morcellation)
• mini-laparotomy myomectomy (scalpel morcellation)
• hysteroscopic myomectomy (intrauterine morcellation)
• uterine artery embolization (no specimen and will delay diagnosis)
• high-intensity focused ultrasound (no specimen and will delay diagnosis)

If abdominal hysterectomy is recommended to women with fibroids, will women be better off?
By focusing exclusively on the risk of LMS, the FDA failed to take into account other risks associated with surgery. Laparoscopic surgery uses small incisions, is performed as an outpatient procedure (or overnight stay), has a faster recovery (2 weeks vs 4–6 weeks for open surgery), and is associated with lower mortality and fewer complications. These benefits of minimally invasive surgery are now well established in gynecologic and general surgery.

Using published best-evidence data, a recent decision analysis¹² showed that, comparing 100,000 women undergoing laparoscopic hysterectomy with 100,000 undergoing open hysterectomy, the group undergoing laparoscopic surgery would experience 20 fewer perioperative deaths, 150 fewer pulmonary or venous embolus, and 4,800 fewer wound infections. Importantly, women having open surgery would have 8,000 fewer quality-of-life years.

A recently published study¹³ found that, in the 8 months following the FDA safety communication, utilization of laparoscopic hysterectomies decreased by 4.1% (P = .005), and abdominal and vaginal hysterectomies increased by 1.7% (P = .112) and 2.4% (P = .012), respectively. Major surgical complications (not including blood transfusions) increased from 2.2% to 2.8% (P = .015), and the rate of hospital readmission within 30 days also increased from 3.4% to 4.2% (P = .025). These observations merit consideration as women weigh the pros and cons of minimally invasive surgery with morcellation versus open surgery. These observations merit consideration as women weigh the pros and cons of minimally invasive surgery with possible morcellation versus open surgery.

Clinical recommendations
Recent attention to surgical options for women with uterine leiomyomas and the risk of an occult leiomyosarcoma are positive developments in that the gynecologic community is re-examining relevant issues. We respectfully suggest that the following clinical recommendations be considered:

• The risk of LMS is higher in older postmenopausal women; greater caution should be exercised prior to recommending morcellation procedures for these women.
• Preoperative consideration of LMS is important. Women aged 35 years and older with irregular uterine bleeding and presumed fibroids should have an endometrial biopsy, which occasionally may detect LMS prior to surgery. Women should have normal results of cervical cancer screening.
• Ultrasound or MRI findings of a large irregular vascular mass, often with irregular anechoic (cystic) areas reflecting necrosis, may cause suspicion of LMS.
• Women wishing minimally invasive procedures with morcellation, including scalpel morcellation via the vagina or mini-laparotomy, or power morcellation using laparoscopic guidance, should understand the potential risk of decreased survival should LMS be present. Open procedures should be offered to all women who are considering minimally invasive procedures for "fibroids."
• Following morcellation, careful inspection for tissue fragments should be undertaken and copious irrigation of the pelvic and abdominal cavities should be performed to minimize the risk of retained tissue.
• Further investigations of a means to identify LMS preoperatively should be supported. Likewise, investigation into the biology of LMS should be funded to better understand the propensity of tissue fragments or cells to implant and grow. With that knowledge, minimally invasive procedures could be avoided for women with LMS and women choosing minimally invasive surgery could be reassured that they do not have LMS.

Respecting women who suffer from leiomyosarcoma, we conclude that the FDA directive was based on a misleading analysis. Consequently, more accurate estimates regarding the prevalence of LMS among women having surgery for fibroids should be issued. Women have a right to self determination. Modification of the FDA's current restrictive guidance regarding power morcellation would empower each woman to consider the pertinent issues and have the freedom to undertake shared decision making with her surgeon in order to select the procedure that is most appropriate for her.

William Parker, MD
Clinical Professor, University of California Los Angeles (UCLA) School of Medicine, Director, Minimally Invasive Gynecologic Surgery, Santa Monica-UCLA Medical Center, Santa Monica, California

Jonathan S. Berek, MD, MMS
Laurie Kraus Lacob Professor and Director, Stanford Women's Cancer Center, Director, Stanford Health Care Communication Program, Chair, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California

Elizabeth Pritts, MD
Wisconsin Fertility Institute, Middleton, Wisconsin

David Olive, MD
Wisconsin Fertility Institute, Middleton, Wisconsin

Andrew M. Kaunitz, MD
University of Florida Research Foundation Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville; Director, Menopause and Gynecologic Ultrasound Services, UF Women’s Health Specialists at Emerson, Jacksonville, Florida.

Eva Chalas, MD
Chief, Division of Gynecologic Oncology, Director, Clinical Cancer Services, Vice-Chair, Department of Obstetrics and Gynecology, Winthrop-University Hospital, Mineola, New York

Daniel Clarke-Pearson, MD
Professor and Chair, Clinical Research, Gynecologic Oncology Program, University of North Carolina at Chapel Hill

Barbara Goff, MD
Professor, Obstetrics and Gynecology, Director, Division of Gynecologic Oncology, University of Washington, Seattle, Washington

Robert E. Bristow, MD, MBA
Professor and Chair, Department of Obstetrics and Gynecology, University of California Irvine School of Medicine, Orange, California

Hugh S. Taylor, MD
Anita O'Keeffe Young Professor and Chair, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicin; Chief of Obstetrics and Gynecology, Yale-New Haven Hospital, New Haven, Connecticut

Robin Farias-Eisner, MD
Chief, Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California Los Angeles

Amanda Nickles Fader, MD
Director, Kelly Gynecologic Oncology Service, Associate Professor of Gynecology and Obstetrics, Director, FJ Montz Fellowship in Gynecologic Oncology, Johns Hopkins Medicine, Baltimore, Maryland

G. Larry Maxwell, MD, COL (ret) US Army
Chairman, Department of Obstetrics and Gynecology, Inova Fairfax Hospital, Falls Church, Virginia; Co-Investigator and Deputy Director of Science, Department of Defense Gynecologic Cancer Translational Research Center of Excellence, Bethesda, Maryland; Professor of Virginia Commonwealth School of Medicine, Richmond, Virginia; and Executive Director of Globeathon to End Women’s Cancer

Scott C. Goodwin, MD
Hasso Brothers Professor and Chairman, Radiological Sciences, University of California Irvine Medical Center, Orange, California

Susan Love, MD, MBA
Dr. Susan Love Research Foundation, Encino, California

William E. Gibbons, MD
Professor and Director, Division of Reproductive Medicine, Director of Fellowship Training, Department of Obstetrics and Gynecology, Baylor College of Medicine; Chief of Reproductive Medicine at the Pavilion For Women at Texas Children’s Hospital, Houston, Texas

Leland J. Foshag, MD
Surgical Oncology, Melanoma and Sarcoma, John Wayne Cancer Institute, Santa Monica, California

Phyllis C. Leppert, MD, PhD
Emerita Professor of Obstetrics and Gynecology, Duke University School of Medicine; President of The Campion Fund, Phyllis and Mark Leppert Foundation for Fertility Research, Durham, North Carolina

Judy Norsigian
Co-founder of Our Bodies, Ourselves, Boston, Massachusetts

Charles W. Nager, MD
Professor and Chairman, Department of Reproductive Medicine, University of California San Diego Health System

Timothy Robert B. Johnson, MD
Arthur F. Thurnau Professor and Chair, Department of Obstetrics and Gynecology, Professor of Women’s Studies, and Research Professor in the Center for Human Growth and Development, University of Michigan, Ann Arbor, Michigan

David S. Guzick, MD, PhD
Senior Vice President of Health Affairs, President of UF Health, University of Florida, Gainesville, Florida

Sawsan As-Sanie, MD, MPH
Assistant Professor and Director, Minimally Invasive Gynecologic Surgery, Fellowship Director of Endometriosis Center, University of Michigan, Ann Arbor, Michigan

Richard J. Paulson, MD
Alia Tutor Chair in Reproductive Medicine, Professor and Vice-Chair, Department of Obstetrics and Gynecology, Chief, Division of Reproductive Endocrinology and Infertility, Keck School of Medicine, University of Southern California, Los Angeles, California

Cindy Farquhar
Professor of Obstetrics and Gynaecology and National Women's Health, University of Auckland, New Zealand

Linda Bradley, MD
Vice Chair of Obstetrics, Gynecology, and Women’s Health Institute, Director of the Fibroid and Menstrual Disorders Center, Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, Ohio.

Stacey A. Scheib, MD
Assistant Professor and Director, Hopkins Multidisciplinary Fibroid Center, Director of Minimally Invasive Gynecologic Surgery, Johns Hopkins Hospital, Baltimore, Maryland

Anton J. Bilchik, MD, PhD
Professor of Surgery, Chief of Medicine at John Wayne Cancer Institute, Santa Monica, California

Laurel W. Rice, MD
Chair, Department of Obstetrics and Gynecology, Professor, Division of Gynecology Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin

Carla Dionne
Founder of National Uterine Fibroid Foundation, Colorado Springs, Colorado

Alison Jacoby, MD
Director, University of California-San Francisco Comprehensive Fibroid Center, Interim Chief, Division of Gynecology, University of California San Francisco

Charles Ascher-Walsh, MD
Director of Gynecology, Urogynecology, and Minimally Invasive Surgery, Mt. Sinai School of Medicine, New York, New York

Sarah J. Kilpatrick, MD, PhD
Chair of Department of Obstetrics and Gynecology, Associate Dean of Faculty Development, Helping Hand of Los Angeles Chair in Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California

G. David Adamson, MD
Clinical Professor, Stanford University School of Medicine, Stanford, California; Past President of the American Society for Reproductive Medicine

Matthew Siedhoff, MD, MSCR
Assistant Professor and Division Director, Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill

Robert Israel, MD
Professor, Department of Obstetrics and Gynecology, Chair, Quality Improvement, Director, Women's Health Clinics and Referrals, LAC+USC Medical Center, Los Angeles, California

Marie Fidela Paraiso, MD
Head, Female Pelvic Medicine & Reconstructive Surgery, Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, Ohio

Michael M. Frumovitz, MD, MPH
Fellowship Program Director, Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas

John R. Lurain, MD
Marcia Stenn Professor of Gynecologic Oncology, Program Director, Fellowship in Gynecologic Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois

Ayman Al-Hendy, MD, PhD
Georgia Regents University Director of Interdisciplinary Translational Research; Medical College of Georgia Assistant Dean for Global Translational Research; Professor and Director, Division of Translational Research, Department of Obstetrics and Gynecology, Georgia Regents Health, Augusta, Georgia

Guy I. Benrubi, MD
Senior Associate Dean for Faculty Affairs, Robert J. Thompson Professor and Chair of Department of Obstetrics and Gynecology, University of Florida College of Medicine – Jacksonville

Steven S. Raman, MD
Professor, Radiology, Urology, and Surgery, Co-director, Fibroid Treatment Program, David Geffen School of Medicine at University of California Los Angeles

Rosanne M. Kho, MD
Associate Professor and Head, Section of Urogynecology and Female Pelvic Medicine & Reconstructive Surgery; Co-Director of Minimally Invasive Gynecologic Surgery Fellowship Program, Columbia University Medical Center, New York, New York

Ted L. Anderson, MD, PhD
Betty and Lonnie S. Burnett Professor and Chair, Obstetrics and Gynecology, Division Director of Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee

R. Kevin Reynolds, MD
The George W. Morley Professor and Chief, Division of Gynecologic Oncology, University of Michigan Health System, Ann Arbor, Michigan

John DeLancey, MD
Norman F. Miller Professor of Obstetrics & Gynecology, University of Michigan Health System, Ann Arbor, Michigan

In November 2014, the FDA ruled that power morcellation was contraindicated in "the majority of women" having surgery for uterine fibroids due to the potential risk of spreading occult uterine sarcoma.¹ Although problems with this ruling were immediately apparent, the passage of time has allowed for more clarity on the related medical issues.

Prevalence of leiomyosarcoma among women having surgery for presumed uterine fibroids
The prevalence of occult leiomyosarcoma among women with fibroids is critical for every patient. All medical procedures have potential risk and the patient's understanding of risk is the foundation of medical decision making.

The FDA estimated that for every 458 women having surgery for fibroids, one woman would be found to have an occult leiomyosarcoma (LMS). We challenge this calculation. To estimate this risk, the FDA searched medical databases using the terms “uterine cancer” AND “hysterectomy or myomectomy.” Because “uterine cancer” was required, studies where cancer was not found or discussed were not identified. Nine studies, all but one of which were retrospective, were analyzed including a non–peer-reviewed Letter to the Editor and an abstract from an unpublished study.^2,3

Additionally, 3 leiomyosarcoma cases identified by the FDA do not meet current pathologic criteria for cancer and would now be classified as benign "atypical" leiomyomas. If atypical leiomyomas and non–peer-reviewed data are excluded, the FDA identified 8 cases of LMS among 12,402 women having surgery for presumed leiomyomas, a prevalence of 1 in 1,550 (0.064%).

Pritts and colleagues⁴ recently published a more rigorous meta-analysis of 133 studies and determined that the prevalence of LMS among women having surgery for presumed fibroids was 1 in 1,960, or 0.051%. All peer-reviewed reports in which surgery was performed for presumed fibroids were analyzed, including reports where cancer was not found. Inclusion criteria required that histopathology results be explicitly provided and available for interpretation. Among the 26 randomized controlled trials analyzed, 1,582 women had surgery for fibroids and none were found to have LMS.

Bojahr and colleagues⁵ recently published a large population-based prospective registry study and reported 2 occult LMS among 8,720 women having surgery for fibroids (0.023%).

In summary: The re-analyzed FDA dataset yields a prevalence of 1 in 1,550 (0.064%); the Pritts study reports a prevalence of 1 in 1,960 (0.051%), with the RCTs having a prevalence of 0; and the Bojahr study reports a prevalence of 2 of 8,720 (0.023%). We acknowledge that with rare events statistical analysis may be uncertain and confidence intervals may be wide. However, these numbers do not support the FDA's estimated prevalence of LMS among women having surgery for presumed fibroids and those at risk for morcellation of an LMS.

Prognosis for women with morcellated LMS
Women with LMS, removed intact without morcellation, have a poor prognosis. Based on SEER data, the 5-year survival of stage I and II LMS is only 61%.⁶ Whether morcellation influences the prognosis of women with LMS is not known, and the biology of this tumor has not been well studied. Distant metastases occur early in the disease process, primarily hematogenous dissemination. Four frequently quoted published studies examine survival following power morcellation. Surprisingly, virtually none of the women in these studies had power morcellation. Furthermore, the data presented in these reports are poorly analyzed and patient numbers are very small.

Park and colleagues⁷ reported only one of the 25 morcellated cases had laparoscopic surgery with power morcellation. Eighteen women had a laparoscopically-assisted vaginal hysterectomy with scalpel morcellation performed through the vagina, one had a vaginal hysterectomy with scalpel-morcellation, and 5 had mini-laparotomy with scalpel morcellation through small lower abdominal incisions. Seventeen of the 25 patients plotted in the published survival curve were referred to the hospital after initial diagnosis or the discovery of a recurrence at another institution. Since the number of nonreferred women with less aggressive disease or without recurrence is not known, it is not possible to determine differences in survival between patients with and without morcellation.

In a study by Perri and colleagues,⁸ none of the patients had power morcellation: 4 women had abdominal myomectomy; 4 had hysteroscopic myomectomy with tissue confined within the uterine cavity; 2 had laparoscopic hysterectomy with scalpel morcellation; 4 had supracervical abdominal hysterectomy with cut-through at the cervix; and 2 had abdominal hysterectomy with injury to the uterus with a sharp instrument.

When comparing the outcomes for women with morcellated and nonmorcellated LMS, Morice and colleagues⁹ found no difference in recurrence rates or overall and disease-free survival at 6 months.

In the only study to compare use of power with scalpel morcellation in women with LMS, Oduyebo and colleagues¹⁰ found no difference in outcomes for the 10 women with power morcellation and 5 with scalpel morcellation followed for a median of 27 months (range, 2–93 months). Notably, a life table analysis of the above studies showed no difference in survival between morcellation methods.¹¹

Of note, laparoscopic-aided morcellation allows the surgeon to inspect the pelvic and abdominal cavities and irrigate and remove tissue fragments under visual control. In contrast, the surgeon cannot visually inspect the peritoneal cavity during vaginal or mini-laparotomy procedures. Morcellation within containment bags has recently been utilized in an attempt to avoid spread of tissue. This method has not yet been proven effective or safe, and there is concern that bags may make morcellation more cumbersome and less safe.

What the FDA restrictions mean for women
The FDA communication states, "the FDA is warning against the use of laparoscopic power morcellators in the majority of women undergoing hysterectomy or myomectomy for uterine fibroids."¹ This statement is not consistent with current evidence.

Moreover, a severe restriction of morcellation, including vaginal and mini-laparotomy morcellation, would limit women with symptomatic leiomyomas to one option: total abdominal hysterectomy. For women with fibroids larger than a 10-week pregnancy size, which most often require either scalpel or power morcellation in order to remove tissue, a ban on morcellation would eliminate the following procedures:

• vaginal hysterectomy (scalpel morcellation)
• mini-laparotomy hysterectomy (scalpel morcellation)
• laparoscopic hysterectomy (scalpel morcellation)
• laparoscopic supracervical hysterectomy (cervix cut-through)
• open supracervical hysterectomy (cervix cut-through)
• laparoscopic myomectomy (power morcellation)
• mini-laparotomy myomectomy (scalpel morcellation)
• hysteroscopic myomectomy (intrauterine morcellation)
• uterine artery embolization (no specimen and will delay diagnosis)
• high-intensity focused ultrasound (no specimen and will delay diagnosis)

If abdominal hysterectomy is recommended to women with fibroids, will women be better off?
By focusing exclusively on the risk of LMS, the FDA failed to take into account other risks associated with surgery. Laparoscopic surgery uses small incisions, is performed as an outpatient procedure (or overnight stay), has a faster recovery (2 weeks vs 4–6 weeks for open surgery), and is associated with lower mortality and fewer complications. These benefits of minimally invasive surgery are now well established in gynecologic and general surgery.

Using published best-evidence data, a recent decision analysis¹² showed that, comparing 100,000 women undergoing laparoscopic hysterectomy with 100,000 undergoing open hysterectomy, the group undergoing laparoscopic surgery would experience 20 fewer perioperative deaths, 150 fewer pulmonary or venous embolus, and 4,800 fewer wound infections. Importantly, women having open surgery would have 8,000 fewer quality-of-life years.

A recently published study¹³ found that, in the 8 months following the FDA safety communication, utilization of laparoscopic hysterectomies decreased by 4.1% (P = .005), and abdominal and vaginal hysterectomies increased by 1.7% (P = .112) and 2.4% (P = .012), respectively. Major surgical complications (not including blood transfusions) increased from 2.2% to 2.8% (P = .015), and the rate of hospital readmission within 30 days also increased from 3.4% to 4.2% (P = .025). These observations merit consideration as women weigh the pros and cons of minimally invasive surgery with morcellation versus open surgery. These observations merit consideration as women weigh the pros and cons of minimally invasive surgery with possible morcellation versus open surgery.

Clinical recommendations
Recent attention to surgical options for women with uterine leiomyomas and the risk of an occult leiomyosarcoma are positive developments in that the gynecologic community is re-examining relevant issues. We respectfully suggest that the following clinical recommendations be considered:

• The risk of LMS is higher in older postmenopausal women; greater caution should be exercised prior to recommending morcellation procedures for these women.
• Preoperative consideration of LMS is important. Women aged 35 years and older with irregular uterine bleeding and presumed fibroids should have an endometrial biopsy, which occasionally may detect LMS prior to surgery. Women should have normal results of cervical cancer screening.
• Ultrasound or MRI findings of a large irregular vascular mass, often with irregular anechoic (cystic) areas reflecting necrosis, may cause suspicion of LMS.
• Women wishing minimally invasive procedures with morcellation, including scalpel morcellation via the vagina or mini-laparotomy, or power morcellation using laparoscopic guidance, should understand the potential risk of decreased survival should LMS be present. Open procedures should be offered to all women who are considering minimally invasive procedures for "fibroids."
• Following morcellation, careful inspection for tissue fragments should be undertaken and copious irrigation of the pelvic and abdominal cavities should be performed to minimize the risk of retained tissue.
• Further investigations of a means to identify LMS preoperatively should be supported. Likewise, investigation into the biology of LMS should be funded to better understand the propensity of tissue fragments or cells to implant and grow. With that knowledge, minimally invasive procedures could be avoided for women with LMS and women choosing minimally invasive surgery could be reassured that they do not have LMS.

Respecting women who suffer from leiomyosarcoma, we conclude that the FDA directive was based on a misleading analysis. Consequently, more accurate estimates regarding the prevalence of LMS among women having surgery for fibroids should be issued. Women have a right to self determination. Modification of the FDA's current restrictive guidance regarding power morcellation would empower each woman to consider the pertinent issues and have the freedom to undertake shared decision making with her surgeon in order to select the procedure that is most appropriate for her.

William Parker, MD
Clinical Professor, University of California Los Angeles (UCLA) School of Medicine, Director, Minimally Invasive Gynecologic Surgery, Santa Monica-UCLA Medical Center, Santa Monica, California

Jonathan S. Berek, MD, MMS
Laurie Kraus Lacob Professor and Director, Stanford Women's Cancer Center, Director, Stanford Health Care Communication Program, Chair, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California

Elizabeth Pritts, MD
Wisconsin Fertility Institute, Middleton, Wisconsin

David Olive, MD
Wisconsin Fertility Institute, Middleton, Wisconsin

Andrew M. Kaunitz, MD
University of Florida Research Foundation Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville; Director, Menopause and Gynecologic Ultrasound Services, UF Women’s Health Specialists at Emerson, Jacksonville, Florida.

Eva Chalas, MD
Chief, Division of Gynecologic Oncology, Director, Clinical Cancer Services, Vice-Chair, Department of Obstetrics and Gynecology, Winthrop-University Hospital, Mineola, New York

Daniel Clarke-Pearson, MD
Professor and Chair, Clinical Research, Gynecologic Oncology Program, University of North Carolina at Chapel Hill

Barbara Goff, MD
Professor, Obstetrics and Gynecology, Director, Division of Gynecologic Oncology, University of Washington, Seattle, Washington

Robert E. Bristow, MD, MBA
Professor and Chair, Department of Obstetrics and Gynecology, University of California Irvine School of Medicine, Orange, California

Hugh S. Taylor, MD
Anita O'Keeffe Young Professor and Chair, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicin; Chief of Obstetrics and Gynecology, Yale-New Haven Hospital, New Haven, Connecticut

Robin Farias-Eisner, MD
Chief, Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California Los Angeles

Amanda Nickles Fader, MD
Director, Kelly Gynecologic Oncology Service, Associate Professor of Gynecology and Obstetrics, Director, FJ Montz Fellowship in Gynecologic Oncology, Johns Hopkins Medicine, Baltimore, Maryland

G. Larry Maxwell, MD, COL (ret) US Army
Chairman, Department of Obstetrics and Gynecology, Inova Fairfax Hospital, Falls Church, Virginia; Co-Investigator and Deputy Director of Science, Department of Defense Gynecologic Cancer Translational Research Center of Excellence, Bethesda, Maryland; Professor of Virginia Commonwealth School of Medicine, Richmond, Virginia; and Executive Director of Globeathon to End Women’s Cancer

Scott C. Goodwin, MD
Hasso Brothers Professor and Chairman, Radiological Sciences, University of California Irvine Medical Center, Orange, California

Susan Love, MD, MBA
Dr. Susan Love Research Foundation, Encino, California

William E. Gibbons, MD
Professor and Director, Division of Reproductive Medicine, Director of Fellowship Training, Department of Obstetrics and Gynecology, Baylor College of Medicine; Chief of Reproductive Medicine at the Pavilion For Women at Texas Children’s Hospital, Houston, Texas

Leland J. Foshag, MD
Surgical Oncology, Melanoma and Sarcoma, John Wayne Cancer Institute, Santa Monica, California

Phyllis C. Leppert, MD, PhD
Emerita Professor of Obstetrics and Gynecology, Duke University School of Medicine; President of The Campion Fund, Phyllis and Mark Leppert Foundation for Fertility Research, Durham, North Carolina

Judy Norsigian
Co-founder of Our Bodies, Ourselves, Boston, Massachusetts

Charles W. Nager, MD
Professor and Chairman, Department of Reproductive Medicine, University of California San Diego Health System

Timothy Robert B. Johnson, MD
Arthur F. Thurnau Professor and Chair, Department of Obstetrics and Gynecology, Professor of Women’s Studies, and Research Professor in the Center for Human Growth and Development, University of Michigan, Ann Arbor, Michigan

David S. Guzick, MD, PhD
Senior Vice President of Health Affairs, President of UF Health, University of Florida, Gainesville, Florida

Sawsan As-Sanie, MD, MPH
Assistant Professor and Director, Minimally Invasive Gynecologic Surgery, Fellowship Director of Endometriosis Center, University of Michigan, Ann Arbor, Michigan

Richard J. Paulson, MD
Alia Tutor Chair in Reproductive Medicine, Professor and Vice-Chair, Department of Obstetrics and Gynecology, Chief, Division of Reproductive Endocrinology and Infertility, Keck School of Medicine, University of Southern California, Los Angeles, California

Cindy Farquhar
Professor of Obstetrics and Gynaecology and National Women's Health, University of Auckland, New Zealand

Linda Bradley, MD
Vice Chair of Obstetrics, Gynecology, and Women’s Health Institute, Director of the Fibroid and Menstrual Disorders Center, Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, Ohio.

Stacey A. Scheib, MD
Assistant Professor and Director, Hopkins Multidisciplinary Fibroid Center, Director of Minimally Invasive Gynecologic Surgery, Johns Hopkins Hospital, Baltimore, Maryland

Anton J. Bilchik, MD, PhD
Professor of Surgery, Chief of Medicine at John Wayne Cancer Institute, Santa Monica, California

Laurel W. Rice, MD
Chair, Department of Obstetrics and Gynecology, Professor, Division of Gynecology Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin

Carla Dionne
Founder of National Uterine Fibroid Foundation, Colorado Springs, Colorado

Alison Jacoby, MD
Director, University of California-San Francisco Comprehensive Fibroid Center, Interim Chief, Division of Gynecology, University of California San Francisco

Charles Ascher-Walsh, MD
Director of Gynecology, Urogynecology, and Minimally Invasive Surgery, Mt. Sinai School of Medicine, New York, New York

Sarah J. Kilpatrick, MD, PhD
Chair of Department of Obstetrics and Gynecology, Associate Dean of Faculty Development, Helping Hand of Los Angeles Chair in Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California

G. David Adamson, MD
Clinical Professor, Stanford University School of Medicine, Stanford, California; Past President of the American Society for Reproductive Medicine

Matthew Siedhoff, MD, MSCR
Assistant Professor and Division Director, Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill

Robert Israel, MD
Professor, Department of Obstetrics and Gynecology, Chair, Quality Improvement, Director, Women's Health Clinics and Referrals, LAC+USC Medical Center, Los Angeles, California

Marie Fidela Paraiso, MD
Head, Female Pelvic Medicine & Reconstructive Surgery, Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, Ohio

Michael M. Frumovitz, MD, MPH
Fellowship Program Director, Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas

John R. Lurain, MD
Marcia Stenn Professor of Gynecologic Oncology, Program Director, Fellowship in Gynecologic Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois

Ayman Al-Hendy, MD, PhD
Georgia Regents University Director of Interdisciplinary Translational Research; Medical College of Georgia Assistant Dean for Global Translational Research; Professor and Director, Division of Translational Research, Department of Obstetrics and Gynecology, Georgia Regents Health, Augusta, Georgia

Guy I. Benrubi, MD
Senior Associate Dean for Faculty Affairs, Robert J. Thompson Professor and Chair of Department of Obstetrics and Gynecology, University of Florida College of Medicine – Jacksonville

Steven S. Raman, MD
Professor, Radiology, Urology, and Surgery, Co-director, Fibroid Treatment Program, David Geffen School of Medicine at University of California Los Angeles

Rosanne M. Kho, MD
Associate Professor and Head, Section of Urogynecology and Female Pelvic Medicine & Reconstructive Surgery; Co-Director of Minimally Invasive Gynecologic Surgery Fellowship Program, Columbia University Medical Center, New York, New York

Ted L. Anderson, MD, PhD
Betty and Lonnie S. Burnett Professor and Chair, Obstetrics and Gynecology, Division Director of Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee

R. Kevin Reynolds, MD
The George W. Morley Professor and Chief, Division of Gynecologic Oncology, University of Michigan Health System, Ann Arbor, Michigan

John DeLancey, MD
Norman F. Miller Professor of Obstetrics & Gynecology, University of Michigan Health System, Ann Arbor, Michigan

More than 9 million American women are estimated to have osteoporosis, making it the most common bone disease and an especially prevalent health problem in postmenopausal women.¹

Osteoporosis causes 2 million fractures every year, leading to major medical consequences for patients.² These fractures are associated with significant morbidity and mortality, often requiring the extended use of long-term care facilities and causing severe disability.

With a rapidly increasing elderly population, the cost of care for osteoporosis is estimated to rise to $25.³ billion by 2025.³ The medical and financial impacts of osteoporosis underscore the need for timely screening and diagnosis and the implementation of effective prevention and treatment strategies. As women’s health care providers, we are the first line of screening and diagnosis and implementation of effective treatment strategies. 

In this “Update on Osteoporosis,” I discuss:

• 2 studies that explore the use of zoledronic acid or denosumab in women with breast cancer undergoing adjuvant therapy with an aromatase inhibitor
• a report of a task force of the American Society for Bone and Mineral Research on the long-term use of bisphosphonate therapy
• a look at the trabecular bone score as a tool to characterize bone strength and overall fracture risk
• the relationship of sarcopenia and body composition with osteoporosis.

Can zoledronic acid or denosumab counter bone loss associated with aromatase inhibitors?

Majithia N, Atherton PJ, Lafky JM, et al. Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy: a 5-year follow-up [published online ahead of print August 23, 2015]. Support Care Cancer. doi:10.1007/s00520-015-2915-2.

Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicenter, randomized, double-blind, placebo-controlled trial. Lancet. 2015;386(9992):433–443.

Every gynecologist and women’s health care provider knows that breast cancer is a prevalent disease. It is also likely to be the most feared entity among our patients.

Aromatase inhibitors (AIs) have been shown consistently to provide benefit for patients with hormone-positive breast cancer and frequently are incorporated into treatment in both the adjuvant and metastatic settings. By inactivating the enzyme responsible for converting androgens to estrogens, AIs reduce plasma estrogen levels. This effect is helpful in the treatment of breast cancer, but it also has consequences for bone mineral density (BMD).

Estrogen promotes the inactivation of osteoclasts, thereby minimizing bone mineral resorption. When plasma levels of estrogen are suppressed, women are susceptible to loss of BMD and development of osteoporosis. This adverse effect has been observed in several clinical trials.^4,5

Study focused on women with low bone mass
Majithia and colleagues set out to explore whether zoledronic acid would prevent loss of BMD in postmenopausal women with preexisting osteopenia or osteoporosis who were initiating adjuvant therapy with the AI letrozole for primary breast cancer.

Sixty postmenopausal women with estrogen-receptor–positive breast cancer and a BMD T-score of –2.0 or less were enrolled. Participants received letrozole 2.5 mg and vitamin D 400 IU daily, calcium 500 mg twice daily, and IV zoledronic acid 4 mg every 6 months for a maximum of 5 years or until disease progression. BMD at the lumbar spine and femoral neck was recorded at the start of the study and annually for 5 years. Patients were evaluated for fractures every 6 months for the duration of the trial.

Findings of Majithia and colleagues. After 5 years of therapy, mean BMD increased by 11.6% (P = .01) at the lumbar spine and by 8.8% (P = .01) at combined sites. Femoral neck BMD increased by 4.2%, although this increase was not significant (P = .23). At the end of the trial, BMDs were consistent with osteoporosis in 7% and osteopenia in 36% of patients. A total of 6 fractures were reported after 417 individual assessments.

Investigators concluded that zoledronic acid appears to prevent further bone loss in postmenopausal breast cancer patients with osteopenia or osteoporosis starting treatment with letrozole. These findings support concurrent initiation of bisphosphonate and AI therapy in this high-risk population.

Denosumab significantly delayed time to first clinical fracture
Gnant and colleagues performed a prospective, double-blind, placebo-controlled, phase 3 trial in which postmenopausal patients with early hormone-receptor– positive breast cancer undergoing treatment with an AI were randomly assigned, in a 1:1 ratio, to denosumab 60 mg or placebo administered subcutaneously every 6 months. The endpoint was time from randomization to first clinical fracture. A total of 3,420 patients were enrolled and studied over 7 years.

Findings of Gnant and colleagues. Patients given denosumab had a significantly delayed time to their first clinical fracture (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.39–0.65), compared with those in the placebo group.

The overall lower number of fractures in the denosumab group (92 vs 176) was similar in all patient subgroups, including patients with a BMD T-score of –1 or higher at baseline (n = 1,872; HR, 0.44; 95% CI, 0.31–0.64; P<.0001) and those with a BMD T-score greater than –1 at baseline (n = 1,548; HR, 0.57; 95% CI, 0.40–0.82; P = .002).

The incidence of adverse events in the safety analysis set (all patients who received at least one dose of the study drug) did not differ between the denosumab (1,366 events, or 80%) and placebo groups (1,344 events, or 79%); nor did the numbers of serious adverse events (521 vs 511, or 30% in each group). The main adverse events were arthralgia and other AI-related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential case of osteonecrosis of the jaw by an international expert panel, no cases were reported.

Differences between the 2 studies
The study with zoledronic acid looked at BMD in a small number of patients with low bone mass over a 1-year time frame. The denosumab study was extremely large and looked at clinical fractures in women with normal as well as low bone mass.

 

What this EVIDENCE means for practice
We all have patients with breast cancer, many of them being treated with an AI. Even those who begin AI therapy with normal bone mass appear to benefit from concomitant therapy with denosumab given subcutaneously every 6 months. 

 

How long should bisphosphonate therapy be continued?

Adler RA, Fuleihan GE, Bauer DC, et al. Managing osteoporosis in patients on long-term bisphosphonate treatment. Report of a task force of the American Society for Bone and Mineral Research [published online ahead of print September 9, 2015]. J Bone Miner Res. doi:10.1002/jbmr.2708.

An osteoporotic fracture occurs every 3 seconds worldwide, and 1 in 3 women will experience a fragility fracture after age 50.^6,7 Solid evidence from randomized, placebo-controlled trials of 3 to 4 years’ duration supports the efficacy of bisphosphonates in decreasing the risk of vertebral fracture (by 40%–70%), hip fracture (by 20%–50%), and nonvertebral fracture (by 15%–39%), depending on the drug, skeletal site, and individual risk profile.⁸ As a result, these drugs have dominated the landscape of osteoporosis therapies for the past 2 decades.

Extension trials have suggested that prolonged bisphosphonate therapy is effective in maintaining BMD as long as 10 years with alendronate, 7 years with risedronate, and 6 years with zoledronic acid, but evidence regarding fracture risk reduction with prolonged therapy is less convincing.^9–11

This report from the American Society for Bone and Mineral Research (ASBMR) examines fracture reduction—not simply BMD efficacy—in 2 trials that explored long-term use of bisphosphonates.

What 2 long-term studies reveal about fracture risk
In the Fracture Intervention Trial Long-Term Extension (FLEX), postmenopausal women who received alendronate for 10 years had fewer clinical vertebral fractures than those who switched to placebo after 5 years.

In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) study extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures than those who switched to placebo after 3 years.

A hip T-score between –2 and –2.5 in FLEX and below –2.5 in the HORIZON extension predicted a beneficial response to continued therapy. Therefore, the ASBMR task force suggests that after 5 years of oral bisphosphonate or 3 years of intravenous therapy, risk reassessment should be considered.

In women at high risk for fracture (such as those who are older, have a low hip T-score or high fracture risk score, have a history of major osteoporotic fracture, or have experienced a fracture during therapy), continuation of treatment for as long as 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered.

The ASBMR task force also found that the risk of atypical femoral fracture—but not osteonecrosis of the jaw—clearly increases with the duration of bisphosphonate therapy. However, such rare events are outweighed by vertebral fracture risk reduction in high-risk patients. For women who do not have a high fracture risk after 3 to 5 years of bisphosphonate therapy, a drug holiday of 2 to 3 years can be considered.

The ASBMR task force acknowledged that its suggested approach for long-term bisphosphonate use is based on limited evidence and was studied only for vertebral fracture reduction in a population that was mostly white and postmenopausal. This approach does not replace the need for clinical judgment. The task force also points out that future trials are unlikely to provide data for the formulation of definitive recommendations.

What this EVIDENCE means for practice
Patients who begin oral bisphosphonate therapy should continue it for 5 years, and those who start intravenous therapy should continue it for 3 years. After that time, the decision concerning continued therapy versus a “drug holiday” requires clinical judgment that takes into account the patient’s level of risk. Notable risk factors include a continued low T-score, older age, and any previous fracture, especially if that fracture occurred during therapy.

 

In the pipeline: The trabecular bone score may help us refine fracture risk prediction

Silva BC, Broy SB, Boutroy S, Schousboe JT, Shepherd JA, Leslie WD. Fracture risk prediction by non-BMD DXA measures: the 2015 ISCD official positions. Part 2: Trabecular bone score. J Clin Densitom. 2015;18(3):309–330.

As measured by dual-energy x-ray absorptiometry (DXA), BMD is a major determinant of bone strength and fracture risk. Although DXA BMD is considered the gold standard for the diagnosis of osteoporosis, most individuals who experience a fragility fracture will have BMD values in the osteopenic or even normal range. This observation implies that the risk of fracture depends on factors other than BMD.

A number of skeletal features other than BMD, such as bone geometry, microarchitecture, mineralization, bone remodeling, and microdamage, contribute to bone strength and overall fracture risk (FIGURE). These features and characteristics of the skeleton that influence bone’s ability to resist fracture are known as bone quality.

 

Important aspects of bone quality—namely, bone microarchitecture and bone remodeling—can be assessed in bone biopsies by histomorphometry and microcomputed tomography. However, iliac crest bone biopsy is an invasive, not widely available procedure, now used primarily as a research tool.

Alternatively, a number of noninvasive imaging modalities, including quantitative computed tomography (QCT) and high-resolution magnetic resonance imaging, can measure bone geometry, microarchitecture, and bone strength and distinguish between individuals with and without fragility fracture. However, compared with standard DXA, these technologies have higher cost, a greater dose of ionizing radiation (QCT), and limited accessibility.

A major challenge, therefore, has been to incorporate into clinical practice a readily available, noninvasive technology that permits improvement in fracture risk prediction beyond that provided by the combination of standard DXA measurements and clinical risk factors. To this end, the trabecular bone score (TBS), a gray-level textural index derived from the lumbar spine DXA image, has been investigated.

How TBS assessment works
The report by Silva and colleagues comes from a task force of the International Society for Clinical Densitometry. TBS is a textual index that evaluates pixel gray-level variations in the lumbar spine DXA image, providing an indirect index of trabecular architecture.

A dense trabecular structure produces a 2-dimensional image with a large number of pixel-value variations of small amplitude and, consequently, a high TBS value. Conversely, a 2-dimensional projection of deteriorated bone architecture produces an image with a low number of pixel-value variations of high amplitude and, therefore, a low TBS.

TBS is measured in the same region of interest as the lumbar spine BMD measurement by dedicated software (TBS iNsight; Medimaps, Plan-les-Ouates, Switzerland). TBS can be obtained from lumbar spine DXA images acquired using the latest generations of GE Lunar (Madison, Wisconsin) or Hologic (Bedford, Massachusetts) densitometers, such as Prodigy and iDXA or Delphi, Horizon, QDR 4500, and Discovery.

The TBS result (which is unitless) is given for each vertebra and for the total lumbar spine (L1–L4). Abnormal vertebrae, including fractured vertebrae and vertebrae with osteoarthritic changes, can be excluded from the TBS analysis, as is done for the BMD measurement.

Silva and colleagues conclude that the ability of TBS to predict fracture risk is partially independent of central DXA BMD, clinical risk factors, and fracture probability estimated by FRAX. Based on these findings, TBS may be used to assess fracture risk in clinical practice and can be used in association with FRAX and BMD to adjust FRAX probability of fracture, guiding treatment decisions.

TBS should not be used alone to determine treatment recommendations, and it is not useful for monitoring bisphosphonate treatment in postmenopausal women with osteoporosis.

 

What this EVIDENCE means for practice
Although TBS is not readily available to most women’s health care clinicians, it is a promising noninvasive software addition to existing DXA equipment. We need to continue to monitor studies of its efficacy and potential to further enhance our understanding of which women should be treated for osteoporosis and which should not. 

 

Is sarcopenia an important piece of the bone health equation?

He H, Liu Y, Tian Q, Papasian CJ, Hu T, Deng HW. Relationship of sarcopenia and body composition with osteoporosis [published online ahead of print August 5, 2015]. Osteoporosis Int.

Sarcopenia is the age-associated loss of muscle mass and strength, and it has a multifactorial basis, including sedentary lifestyle, changing endocrine function, chronic disease, inflammation, insulin resistance, and nutritional deficiency. Sarcopenia may result in adverse outcomes such as physical disability, poor quality of life, escalated costs of health care, and increased mortality. The prevalence of sarcopenia is reported to range from 5% to 13% in adults aged 60 to 70 years and from 11% to 50% in people older than 80 years.¹²

The pathophysiology and etiology of sarcopenia and osteoporosis, and the relationship between them, are complicated and multifactorial. Recent studies have shown that muscle and bone share some common genetic, nutritional, lifestyle, and hormonal determinants, and that body composition and muscle strength are correlated with bone density.^13,14 In the elderly, decreased muscle mass and increased fat mass may contribute to difficulties with physical function.

Exploring the relationship between sarcopenia and osteoporosis
He and colleagues investigated this relationship in a cohort of 17,891 people. Lean mass and grip strength were positively associated with BMD. People with sarcopenia were twice as likely as individuals without sarcopenia to have osteoporosis.

People of black, white, and Chinese heritage were analyzed. Sarcopenia was defined by relative appendicular skeletal muscle mass (RASM) cut points. RASM is calculated as lean mass (as measured by DXA) divided by height squared. For this study, He and colleagues defined sarcopenia as RASM more than 2 standard deviations below the mean of young male and female reference groups. The current objective cut points for sarcopenia in men and women are RASM of 7.26 kg/m² or less and RASM of 5.45 kg/m² or lower, respectively.

These criteria for sarcopenia are based on previous studies in people of white and black race.^15,16 Because of ethnic differences in body composition, these criteria do not appear to be applicable to Chinese individuals. An earlier study¹⁷ established the cutoff values of 6.08 kg/m² and 4.79 kg/m² for sarcopenia in healthy Chinese men and women, respectively, and these criteria were used for the diagnosis of sarcopenia in the Chinese sample.

Fat mass also was measured by DXA. BMD was positively associated with lean mass and negatively associated with fat mass. Grip strength was significantly associated with a higher BMD. Each standard deviation increase in RASM resulted in a risk reduction of approximately 37% for osteopenia or osteoporosis (odds ratio [OR], 0.63; 95% CI, 0.59−0.66).

Individuals with sarcopenia, as defined by RASM, were twice as likely as patients without sarcopenia to have osteopenia or osteoporosis (OR, 2.04; 95% CI, 1.61−2.60). Similarly, people with sarcopenia (low muscle mass and grip strength) were approximately 1.8 times more likely than individuals with normal muscle mass and grip strength to have osteopenia or osteoporosis (OR, 1.87; 95% CI, 1.09−3.20).

He and colleagues concluded that high lean mass and muscle strength were positively associated with BMD. Sarcopenia is associated with low BMD and osteoporosis.

 

What this EVIDENCE means for practice
We may be approaching an era in which simple measurement of BMD will be augmented with concurrent DXA measurement of lean mass and fat mass. This may help us better identify patients at risk for fracture and disability, for whom intervention may prove valuable.

 

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

More than 9 million American women are estimated to have osteoporosis, making it the most common bone disease and an especially prevalent health problem in postmenopausal women.¹

Osteoporosis causes 2 million fractures every year, leading to major medical consequences for patients.² These fractures are associated with significant morbidity and mortality, often requiring the extended use of long-term care facilities and causing severe disability.

With a rapidly increasing elderly population, the cost of care for osteoporosis is estimated to rise to $25.³ billion by 2025.³ The medical and financial impacts of osteoporosis underscore the need for timely screening and diagnosis and the implementation of effective prevention and treatment strategies. As women’s health care providers, we are the first line of screening and diagnosis and implementation of effective treatment strategies. 

In this “Update on Osteoporosis,” I discuss:

• 2 studies that explore the use of zoledronic acid or denosumab in women with breast cancer undergoing adjuvant therapy with an aromatase inhibitor
• a report of a task force of the American Society for Bone and Mineral Research on the long-term use of bisphosphonate therapy
• a look at the trabecular bone score as a tool to characterize bone strength and overall fracture risk
• the relationship of sarcopenia and body composition with osteoporosis.

Can zoledronic acid or denosumab counter bone loss associated with aromatase inhibitors?

Majithia N, Atherton PJ, Lafky JM, et al. Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy: a 5-year follow-up [published online ahead of print August 23, 2015]. Support Care Cancer. doi:10.1007/s00520-015-2915-2.

Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicenter, randomized, double-blind, placebo-controlled trial. Lancet. 2015;386(9992):433–443.

Every gynecologist and women’s health care provider knows that breast cancer is a prevalent disease. It is also likely to be the most feared entity among our patients.

Aromatase inhibitors (AIs) have been shown consistently to provide benefit for patients with hormone-positive breast cancer and frequently are incorporated into treatment in both the adjuvant and metastatic settings. By inactivating the enzyme responsible for converting androgens to estrogens, AIs reduce plasma estrogen levels. This effect is helpful in the treatment of breast cancer, but it also has consequences for bone mineral density (BMD).

Estrogen promotes the inactivation of osteoclasts, thereby minimizing bone mineral resorption. When plasma levels of estrogen are suppressed, women are susceptible to loss of BMD and development of osteoporosis. This adverse effect has been observed in several clinical trials.^4,5

Study focused on women with low bone mass
Majithia and colleagues set out to explore whether zoledronic acid would prevent loss of BMD in postmenopausal women with preexisting osteopenia or osteoporosis who were initiating adjuvant therapy with the AI letrozole for primary breast cancer.

Sixty postmenopausal women with estrogen-receptor–positive breast cancer and a BMD T-score of –2.0 or less were enrolled. Participants received letrozole 2.5 mg and vitamin D 400 IU daily, calcium 500 mg twice daily, and IV zoledronic acid 4 mg every 6 months for a maximum of 5 years or until disease progression. BMD at the lumbar spine and femoral neck was recorded at the start of the study and annually for 5 years. Patients were evaluated for fractures every 6 months for the duration of the trial.

Findings of Majithia and colleagues. After 5 years of therapy, mean BMD increased by 11.6% (P = .01) at the lumbar spine and by 8.8% (P = .01) at combined sites. Femoral neck BMD increased by 4.2%, although this increase was not significant (P = .23). At the end of the trial, BMDs were consistent with osteoporosis in 7% and osteopenia in 36% of patients. A total of 6 fractures were reported after 417 individual assessments.

Investigators concluded that zoledronic acid appears to prevent further bone loss in postmenopausal breast cancer patients with osteopenia or osteoporosis starting treatment with letrozole. These findings support concurrent initiation of bisphosphonate and AI therapy in this high-risk population.

Denosumab significantly delayed time to first clinical fracture
Gnant and colleagues performed a prospective, double-blind, placebo-controlled, phase 3 trial in which postmenopausal patients with early hormone-receptor– positive breast cancer undergoing treatment with an AI were randomly assigned, in a 1:1 ratio, to denosumab 60 mg or placebo administered subcutaneously every 6 months. The endpoint was time from randomization to first clinical fracture. A total of 3,420 patients were enrolled and studied over 7 years.

Findings of Gnant and colleagues. Patients given denosumab had a significantly delayed time to their first clinical fracture (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.39–0.65), compared with those in the placebo group.

The overall lower number of fractures in the denosumab group (92 vs 176) was similar in all patient subgroups, including patients with a BMD T-score of –1 or higher at baseline (n = 1,872; HR, 0.44; 95% CI, 0.31–0.64; P<.0001) and those with a BMD T-score greater than –1 at baseline (n = 1,548; HR, 0.57; 95% CI, 0.40–0.82; P = .002).

The incidence of adverse events in the safety analysis set (all patients who received at least one dose of the study drug) did not differ between the denosumab (1,366 events, or 80%) and placebo groups (1,344 events, or 79%); nor did the numbers of serious adverse events (521 vs 511, or 30% in each group). The main adverse events were arthralgia and other AI-related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential case of osteonecrosis of the jaw by an international expert panel, no cases were reported.

Differences between the 2 studies
The study with zoledronic acid looked at BMD in a small number of patients with low bone mass over a 1-year time frame. The denosumab study was extremely large and looked at clinical fractures in women with normal as well as low bone mass.

 

What this EVIDENCE means for practice
We all have patients with breast cancer, many of them being treated with an AI. Even those who begin AI therapy with normal bone mass appear to benefit from concomitant therapy with denosumab given subcutaneously every 6 months. 

 

How long should bisphosphonate therapy be continued?

Adler RA, Fuleihan GE, Bauer DC, et al. Managing osteoporosis in patients on long-term bisphosphonate treatment. Report of a task force of the American Society for Bone and Mineral Research [published online ahead of print September 9, 2015]. J Bone Miner Res. doi:10.1002/jbmr.2708.

An osteoporotic fracture occurs every 3 seconds worldwide, and 1 in 3 women will experience a fragility fracture after age 50.^6,7 Solid evidence from randomized, placebo-controlled trials of 3 to 4 years’ duration supports the efficacy of bisphosphonates in decreasing the risk of vertebral fracture (by 40%–70%), hip fracture (by 20%–50%), and nonvertebral fracture (by 15%–39%), depending on the drug, skeletal site, and individual risk profile.⁸ As a result, these drugs have dominated the landscape of osteoporosis therapies for the past 2 decades.

Extension trials have suggested that prolonged bisphosphonate therapy is effective in maintaining BMD as long as 10 years with alendronate, 7 years with risedronate, and 6 years with zoledronic acid, but evidence regarding fracture risk reduction with prolonged therapy is less convincing.^9–11

This report from the American Society for Bone and Mineral Research (ASBMR) examines fracture reduction—not simply BMD efficacy—in 2 trials that explored long-term use of bisphosphonates.

What 2 long-term studies reveal about fracture risk
In the Fracture Intervention Trial Long-Term Extension (FLEX), postmenopausal women who received alendronate for 10 years had fewer clinical vertebral fractures than those who switched to placebo after 5 years.

In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) study extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures than those who switched to placebo after 3 years.

A hip T-score between –2 and –2.5 in FLEX and below –2.5 in the HORIZON extension predicted a beneficial response to continued therapy. Therefore, the ASBMR task force suggests that after 5 years of oral bisphosphonate or 3 years of intravenous therapy, risk reassessment should be considered.

In women at high risk for fracture (such as those who are older, have a low hip T-score or high fracture risk score, have a history of major osteoporotic fracture, or have experienced a fracture during therapy), continuation of treatment for as long as 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered.

The ASBMR task force also found that the risk of atypical femoral fracture—but not osteonecrosis of the jaw—clearly increases with the duration of bisphosphonate therapy. However, such rare events are outweighed by vertebral fracture risk reduction in high-risk patients. For women who do not have a high fracture risk after 3 to 5 years of bisphosphonate therapy, a drug holiday of 2 to 3 years can be considered.

The ASBMR task force acknowledged that its suggested approach for long-term bisphosphonate use is based on limited evidence and was studied only for vertebral fracture reduction in a population that was mostly white and postmenopausal. This approach does not replace the need for clinical judgment. The task force also points out that future trials are unlikely to provide data for the formulation of definitive recommendations.

What this EVIDENCE means for practice
Patients who begin oral bisphosphonate therapy should continue it for 5 years, and those who start intravenous therapy should continue it for 3 years. After that time, the decision concerning continued therapy versus a “drug holiday” requires clinical judgment that takes into account the patient’s level of risk. Notable risk factors include a continued low T-score, older age, and any previous fracture, especially if that fracture occurred during therapy.

 

In the pipeline: The trabecular bone score may help us refine fracture risk prediction

Silva BC, Broy SB, Boutroy S, Schousboe JT, Shepherd JA, Leslie WD. Fracture risk prediction by non-BMD DXA measures: the 2015 ISCD official positions. Part 2: Trabecular bone score. J Clin Densitom. 2015;18(3):309–330.

As measured by dual-energy x-ray absorptiometry (DXA), BMD is a major determinant of bone strength and fracture risk. Although DXA BMD is considered the gold standard for the diagnosis of osteoporosis, most individuals who experience a fragility fracture will have BMD values in the osteopenic or even normal range. This observation implies that the risk of fracture depends on factors other than BMD.

A number of skeletal features other than BMD, such as bone geometry, microarchitecture, mineralization, bone remodeling, and microdamage, contribute to bone strength and overall fracture risk (FIGURE). These features and characteristics of the skeleton that influence bone’s ability to resist fracture are known as bone quality.

 

Important aspects of bone quality—namely, bone microarchitecture and bone remodeling—can be assessed in bone biopsies by histomorphometry and microcomputed tomography. However, iliac crest bone biopsy is an invasive, not widely available procedure, now used primarily as a research tool.

Alternatively, a number of noninvasive imaging modalities, including quantitative computed tomography (QCT) and high-resolution magnetic resonance imaging, can measure bone geometry, microarchitecture, and bone strength and distinguish between individuals with and without fragility fracture. However, compared with standard DXA, these technologies have higher cost, a greater dose of ionizing radiation (QCT), and limited accessibility.

A major challenge, therefore, has been to incorporate into clinical practice a readily available, noninvasive technology that permits improvement in fracture risk prediction beyond that provided by the combination of standard DXA measurements and clinical risk factors. To this end, the trabecular bone score (TBS), a gray-level textural index derived from the lumbar spine DXA image, has been investigated.

How TBS assessment works
The report by Silva and colleagues comes from a task force of the International Society for Clinical Densitometry. TBS is a textual index that evaluates pixel gray-level variations in the lumbar spine DXA image, providing an indirect index of trabecular architecture.

A dense trabecular structure produces a 2-dimensional image with a large number of pixel-value variations of small amplitude and, consequently, a high TBS value. Conversely, a 2-dimensional projection of deteriorated bone architecture produces an image with a low number of pixel-value variations of high amplitude and, therefore, a low TBS.

TBS is measured in the same region of interest as the lumbar spine BMD measurement by dedicated software (TBS iNsight; Medimaps, Plan-les-Ouates, Switzerland). TBS can be obtained from lumbar spine DXA images acquired using the latest generations of GE Lunar (Madison, Wisconsin) or Hologic (Bedford, Massachusetts) densitometers, such as Prodigy and iDXA or Delphi, Horizon, QDR 4500, and Discovery.

The TBS result (which is unitless) is given for each vertebra and for the total lumbar spine (L1–L4). Abnormal vertebrae, including fractured vertebrae and vertebrae with osteoarthritic changes, can be excluded from the TBS analysis, as is done for the BMD measurement.

Silva and colleagues conclude that the ability of TBS to predict fracture risk is partially independent of central DXA BMD, clinical risk factors, and fracture probability estimated by FRAX. Based on these findings, TBS may be used to assess fracture risk in clinical practice and can be used in association with FRAX and BMD to adjust FRAX probability of fracture, guiding treatment decisions.

TBS should not be used alone to determine treatment recommendations, and it is not useful for monitoring bisphosphonate treatment in postmenopausal women with osteoporosis.

 

What this EVIDENCE means for practice
Although TBS is not readily available to most women’s health care clinicians, it is a promising noninvasive software addition to existing DXA equipment. We need to continue to monitor studies of its efficacy and potential to further enhance our understanding of which women should be treated for osteoporosis and which should not. 

 

Is sarcopenia an important piece of the bone health equation?

He H, Liu Y, Tian Q, Papasian CJ, Hu T, Deng HW. Relationship of sarcopenia and body composition with osteoporosis [published online ahead of print August 5, 2015]. Osteoporosis Int.

Sarcopenia is the age-associated loss of muscle mass and strength, and it has a multifactorial basis, including sedentary lifestyle, changing endocrine function, chronic disease, inflammation, insulin resistance, and nutritional deficiency. Sarcopenia may result in adverse outcomes such as physical disability, poor quality of life, escalated costs of health care, and increased mortality. The prevalence of sarcopenia is reported to range from 5% to 13% in adults aged 60 to 70 years and from 11% to 50% in people older than 80 years.¹²

The pathophysiology and etiology of sarcopenia and osteoporosis, and the relationship between them, are complicated and multifactorial. Recent studies have shown that muscle and bone share some common genetic, nutritional, lifestyle, and hormonal determinants, and that body composition and muscle strength are correlated with bone density.^13,14 In the elderly, decreased muscle mass and increased fat mass may contribute to difficulties with physical function.

Exploring the relationship between sarcopenia and osteoporosis
He and colleagues investigated this relationship in a cohort of 17,891 people. Lean mass and grip strength were positively associated with BMD. People with sarcopenia were twice as likely as individuals without sarcopenia to have osteoporosis.

People of black, white, and Chinese heritage were analyzed. Sarcopenia was defined by relative appendicular skeletal muscle mass (RASM) cut points. RASM is calculated as lean mass (as measured by DXA) divided by height squared. For this study, He and colleagues defined sarcopenia as RASM more than 2 standard deviations below the mean of young male and female reference groups. The current objective cut points for sarcopenia in men and women are RASM of 7.26 kg/m² or less and RASM of 5.45 kg/m² or lower, respectively.

These criteria for sarcopenia are based on previous studies in people of white and black race.^15,16 Because of ethnic differences in body composition, these criteria do not appear to be applicable to Chinese individuals. An earlier study¹⁷ established the cutoff values of 6.08 kg/m² and 4.79 kg/m² for sarcopenia in healthy Chinese men and women, respectively, and these criteria were used for the diagnosis of sarcopenia in the Chinese sample.

Fat mass also was measured by DXA. BMD was positively associated with lean mass and negatively associated with fat mass. Grip strength was significantly associated with a higher BMD. Each standard deviation increase in RASM resulted in a risk reduction of approximately 37% for osteopenia or osteoporosis (odds ratio [OR], 0.63; 95% CI, 0.59−0.66).

Individuals with sarcopenia, as defined by RASM, were twice as likely as patients without sarcopenia to have osteopenia or osteoporosis (OR, 2.04; 95% CI, 1.61−2.60). Similarly, people with sarcopenia (low muscle mass and grip strength) were approximately 1.8 times more likely than individuals with normal muscle mass and grip strength to have osteopenia or osteoporosis (OR, 1.87; 95% CI, 1.09−3.20).

He and colleagues concluded that high lean mass and muscle strength were positively associated with BMD. Sarcopenia is associated with low BMD and osteoporosis.

 

What this EVIDENCE means for practice
We may be approaching an era in which simple measurement of BMD will be augmented with concurrent DXA measurement of lean mass and fat mass. This may help us better identify patients at risk for fracture and disability, for whom intervention may prove valuable.

 

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.