Open letter to the FDA regarding its ruling on power morcellation

On December 8, 48 gynecologists, gynecologic oncologists, surgical oncologists, department chairs, and women’s health advocates sent an open letter to the FDA, asking the agency to rescind or revise its recent ruling contraindicating power morcellation in "the majority of women" having surgery for uterine fibroids due to the potential risk of spreading occult uterine sarcoma.

Two Contemporary OB/GYN editorial board members signed their names to the letter. They tell us why below. The full text of the open letter follows their comments.

Board member John O DeLancey, MD:

“At the time of the original decision, the FDA was responding to the information provided to them. The need for such a decision was probably highly influenced by the media’s decision to make this a major issue. That analysis focused primarily on a single issue: the risk of cancer dissemination. On review of more comprehensive information, it is apparent that the risk of spreading cancer is lower than previously thought. In addition, a more complete analysis of the consequences of banning morcellation-that large numbers of women would suffer by increasing the number of women subjected to open laparotomy and its increased risks compared with laparoscopy-has been possible. One would hope that this more complete analysis would result in reconsideration of this important issue.”

Board member Sarah J Kilpatrick, MD, PhD:

“Although I understand that the FDA’s intent in its statement on morcellation was to protect women, unfortunately they failed to fully assess available data on incidence of uterine sarcoma, and the major impact of restricting the appropriate use of morcellation. If appropriate use of morcellation for minimally invasive removal of fibroids is restricted, hundreds of women will be unnecessarily subjected to major open surgery with far more risks to them than the risk of an occult uterine sarcoma.”

NEXT: The letter sent to the US Food and Drug Administration

An open letter to the FDA regarding the use of morcellation procedures for women having surgery for presumed uterine fibroids.

In November, 2014 the FDA ruled that power morcellation was contra-indicated in "the majority of women" having surgery for uterine fibroids due to the potential risk of spreading occult uterine sarcoma. 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. (Leung, Rowland) Additionally, three "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 et al. 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 control trials analyzed, 1,582 women had surgery for fibroids and none were found to have LMS. Bojahr et al., 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 RCT’s having a prevalence of 0 and the Bojahr study reported 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 a leiomyosarcoma.

Prognosis for women with morcellated LMS

Leiomyosarcoma, 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%. (Kosary) Whether morcellation influences the prognosis of women with LMS is not known and the biology of this tumor has not been well studied. Distant metastasis 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, et. al. 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 non-referred 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 et. al., none of the patients had power-morcellation. Four women had an abdominal myomectomy, four had a hysteroscopic myomectomy with tissue confined within the uterine cavity, two had a laparoscopic hysterectomy with scalpel-morcellation, four had a supra-cervical abdominal hysterectomy with cut-through at the cervix and two had an abdominal hysterectomy with injury to the uterus with a sharp instrument. When comparing the outcomes for women with morcellated and non-morcellated LMS, Morice et. al., found no difference in recurrence rates or over-all and disease-free survival at six months. In the only study to compare use of power- with scalpel-morcellation in women with LMS, Oduyebo et. al. found no difference in outcomes for the 10 women with power-morcellation and five with scalpel-morcellation followed for a median of 27 months (range, 2-93). Notably, a life table analysis of the above studies showed no difference in survival between morcellation methods. (Pritts)

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 have recently been utilized in an attempt to avoid spread of tissue. These methods have 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 -morcellators in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids." 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 supra-cervical hysterectomy (cervix cut-through)

·      open supra-cervical 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 out-patient procedure (or overnight stay), has a faster recovery (2 weeks versus 4-6 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 analysis showed that, comparing 100,000 women having laparoscopic hysterectomy with 100,000 having open hysterectomy, the group having laparoscopic surgery would experience 20 fewer peri-operative deaths, 150 fewer women would have a pulmonary or venous embolus and 4,800 fewer women would have a wound infection. (Seidhoff) Importantly, women having open surgery would have 8,000 fewer quality-of-life years. A recently published study found that in the eight months following the FDA safety communication, utilization of laparoscopic hysterectomies decreased by 4.1% (p=0.005) and both abdominal and vaginal hysterectomies increased (1.7%, p =0.112 and 2.4%, p=0.012, respectively). (Harris) Major surgical complications (not including blood transfusions) significantly increased from 2.2% to 2.8% (p=0.015), and the rate of hospital readmission within 30 days also increased from 3.4% to 4.2% (p=0.025). 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 vs. open surgery.

Clinical Recommendations

Recent attention to surgical options for women with uterine leiomyomas and the risk of an occult leiomyosarcoma is a positive development 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 post-menopausal women and greater caution should be exercised prior to recommending morcellation procedures for these women.

·      Preoperative consideration of LMS is important and women age 35 or 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 pre-operatively 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 re-assured 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 which is most appropriate for her.

William Parker, MD

Clinical Professor

UCLA School of Medicine

Director, Minimally Invasive Gynecologic Surgery

Santa Monica-UCLA Medical Center

Jonathan S Berek, MD, MMS

Laurie Kraus Lacob Professor

Director, Stanford Women's Cancer Center

Director, Stanford Health Care Communication Program

Chair, Department of Obstetrics and Gynecology

Stanford University School of Medicine

Elizabeth Pritts, MD

Wisconsin Fertility Institute

Middleton, WI

David Olive, MD

Wisconsin Fertility Institute

Middleton, WI

Andrew M. Kaunitz, MD

University of Florida Research Foundation Professor

Associate Chair, Department of Obstetrics and Gynecology

University of Florida College of Medicine–Jacksonville

Eva Chalas, MD, FACOG, FACS

Chief, Division of Gynecologic Oncology

Director of Clinical Cancer Services

Vice-Chair, Department of Obstetrics and Gynecology

Winthrop-University Hospital

Daniel Clarke-Pearson, MD

Professor and Chair

Clinical Research, Gynecologic Oncology Program

UNC-Chapel Hill

Barbara Goff, MD

Professor of Obstetrics and Gynecology

Director, Division of Gynecologic Oncology

University of Washington

Seattle, WA

Robert Bristow, MD

Professor and Chair

Department of Obstetrics and Gynecology

UC Irvine School of Medicine

Hugh S. Taylor, M.D.

Anita O'Keeffe Young Professor and Chair Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine

Chief of Obstetrics and Gynecology

Yale-New Haven Hospital

Robin Farias-Eisner, MD

Chief of Gynecology and Gynecologic Oncology

Department of Obstetrics and Gynecology

David Geffen School of Medicine at UCLA

Amanda Nickles Fader, MD

Director of the Kelly Gynecologic Oncology Service

Director, F.J. Montz Fellowship in Gynecologic Oncology

Johns Hopkins Medicine

G Larry Maxwell, MD, FACOG, COL(ret) U.S. Army

Chairman, Department of Obstetrics and Gynecology, Inova Fairfax Hospital

Co-P.I., DOD Gynecologic Cancer Translational Research Center of Excellence

Professor, Virginia Commonwealth School of Medicine

Executive Director, Globe-athon to End Women’s Cancer

Scott C Goodwin, MD

Hasso Brothers Professor and Chairman, Radiological Sciences

University of California, Irvine

Susan Love, MD

Dr. Susan Love Research Foundation

William E Gibbons, MD

Professor

Director, Division of Reproductive Medicine

Director, Fellowship Training

Department of Obstetrics and Gynecology

Baylor College of Medicine

Chief, Reproductive Medicine the Pavilion For Women at Texas Children’s Hospital

Houston, Texas

Leland J. Foshag, M.D., FACS

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, The Campion Fund, Phyllis and Mark Leppert Foundation for Fertility Research

Judy Norsigian

Co-founder, Our Bodies, Ourselves

Boston, Mass

Charles W. Nager, MD

Professor and Chairman

Department of Reproductive Medicine

UC San Diego Health System

Timothy Johnson, MD

Chair, Department of Obstetrics and Gynecology, University of Michigan

Arthur F. Thurnau Professor, Professor of Women’s Studies, and Research Professor in the Center for Human Growth and Development

David S. Guzick, MD, PhD

Senior Vice President, Health Affairs

President, UF Health

University of Florida

Sawsan As-Sanie, MD MPH

Assistant Professor

Director, Minimally Invasive Gynecologic Surgery and Fellowship

Director, Endometriosis Center

University of 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

Professor Cindy Farquhar

Department of Obstetrics and Gynaecology and National Women's Health

University of Auckland, NZ

Linda Bradley, MD

Vice Chair of Obstetrics, Gynecology and Women’s Health Institute

Director of The Fibroid and Menstrual Disorders Center

Cleveland Clinic

Dept of Obstetrics and Gynecology

Stacey A. Scheib, MD

Assistant Professor

Director of the Hopkins Multidisciplinary Fibroid Center

Director of Minimally Invasive Gynecologic Surgery

Johns Hopkins Hospital

Anton J. Bilchik, MD, PhD, FACS

Professor of Surgery

Chief of Medicine at John Wayne Cancer Institute

Santa Monica, California

Laurel W. Rice, MD

Chair of the Department of Obstetrics and Gynecology

Professor, Division of Gynecology Oncology

University of Wisconsin-Madison School of Medicine and Public Health

Carla Dionne

Founder, National Uterine Fibroid Foundation

Alison Jacoby, MD

Director, UCSF Comprehensive Fibroid Center

Interim Chief, Division of Gynecology

University of California, San Francisco

Charles Ascher-Walsh, MD

Director of Gynecology, Urogynecology, MIS

Mt. Sinai School of Medicine

New York, NY

Sarah J. Kilpatrick, MD, PhD

Chair, Department of Obstetrics and Gynecology

Associate Dean, 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

Past President of the American Society for Reproductive Medicine

Matthew Siedhoff, MD MSCR

University of North Carolina at Chapel Hill

Obstetrics & Gynecology

Minimally Invasive Gynecologic Surgery, Director

Robert Israel, M.D

Professor, Department of OB/GYN
Chair, Quality Improvement 
Director, Women's Health Clinics and Referrals, LAC+USC Medical Center

Marie Fidela Paraiso, MD

Head, Female Pelvic Medicine & Reconstructive Surgery

Cleveland Clinic, OH

Michael M. Frumovitz, M. D., M.P.H., FACOG, FACS

Fellowship Program Director

Department of Gynecologic Oncology and Reproductive Medicine

The University of Texas MD Anderson Cancer Center

John R Lurain, MD

Marcia Stenn Professor of Gynecologic Oncology

Program director for the fellowship in gynecologic oncology

Northwestern University Feinberg School of Medicine

Ayman Al-Hendy MD PhD FRCSC FACOG CCRP

GRU Director of Interdisciplinary Translational Research

MCG Assistant Dean for Global Translational Research

Professor and Director

Division of Translational Research

Department of Obstetrics and Gynecology

Medical College of Georgia

Georgia Regents University

Guy I. Benrubi, M.D.

Senior Associate Dean for Faculty Affairs,

Robert J. Thompson Professor and Chair,

Department of Obstetrics and Gynecology

University of Florida College of Medicine - Jacksonville

Steven S. Raman, MD

Professor of Radiology, Urology, and Surgery

Co-director of the Fibroid Treatment Program

David Geffen School of Medicine at UCLA

Rosanne M Kho MD

Associate Professor

Head, Section of Urogynecology and FPMRS

Co-Director, MIGS Fellowship Program

Columbia University Medical Center

New York, NY

Ted L. Anderson, M.D., Ph.D.

Betty and Lonnie S. Burnett Professor and Chair, Obstetrics and Gynecology

Division Director, Gynecology

Vanderbilt University School of Medicine

R. Kevin Reynolds, MD, FACS, FACOG

The George W. Morley Professor and Chief

Division of Gynecologic Oncology

University of Michigan

Ann Arbor Michigan

John DeLancey, MD

Norman F. Miller Professor of Obstetrics & Gynecology

University of Michigan Health System

All institutional affiliations are for identification purposes only

No signee has declared a conflict of interest

References

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