- Email: [email protected]
Laparoscopic Ovarian Transposition Before Pelvic Cancer Treatment: Ovarian Function and Fertility Preservation
Accepted Manuscript Laparoscopic Ovarian Transposition Before Pelvic Cancer Treatment: Ovarian Function and Fertility Preservation Nash S. Moawad, M.D., M.S., Estefania Santamaria, B.S., Alice Rhoton-Vlasak, M.D., Judith L. Lightsey, M.D. PII:
S1553-4650(16)31038-X
DOI:
10.1016/j.jmig.2016.08.831
Reference:
JMIG 2943
To appear in:
The Journal of Minimally Invasive Gynecology
Received Date: 1 July 2016 Revised Date:
24 August 2016
Accepted Date: 27 August 2016
Please cite this article as: Moawad NS, Santamaria E, Rhoton-Vlasak A, Lightsey JL, Laparoscopic Ovarian Transposition Before Pelvic Cancer Treatment: Ovarian Function and Fertility Preservation, The Journal of Minimally Invasive Gynecology (2016), doi: 10.1016/j.jmig.2016.08.831. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Moawad 1 Laparoscopic Ovarian Transposition Before Pelvic Cancer Treatment: Ovarian Function and Fertility Preservation Nash S. Moawad, M.D., M.S.1; Estefania Santamaria, B.S.2; Alice Rhoton-Vlasak, M.D.3; Judith L. Lightsey, M.D.4
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Associate Professor Minimally-Invasive Gynecologic Surgery
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Department of Obstetrics and Gynecology
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University of Florida College of Medicine
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P.O. Box 100294
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Gainesville, FL 32610
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Office: 352-273-7660 Fax: 352-392-3498
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[email protected]
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Corresponding Author: Nash S. Moawad, MD, MS, FACOG
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Disclosure: The authors report no financial disclosures or conflict or interest related
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to this study. 1. 2. 3. 4.
Section of Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, University of Florida College of Medicine University of Florida College of Medicine Division of Reproductive Endocrinology & Infertility, Department of Obstetrics and Gynecology, University of Florida College of Medicine Department of Radiation Oncology, University of Florida College of Medicine
ACCEPTED MANUSCRIPT Moawad 2 Precis: We describe ovarian transposition—an underused procedure in young
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women diagnosed with pelvic cancers—its indications, technique and outcomes in
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the context of ovarian function and fertility preservation following
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chemoradiotherapy.
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ACCEPTED MANUSCRIPT Moawad 3 Abstract
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OBJECTIVE: To summarize available studies with respect to indications for ovarian
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transposition and patient outcomes post-procedure in the context of ovarian
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function and fertility preservation following radiation and chemotherapy.
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DATA SOURCES: We conducted an electronic search of research articles published
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in English without date restriction using PubMed and Cochrane databases.
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METHODS OF STUDY SELECTION: Of the 79 studies initially identified, 55 were
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selected after limiting the review to those case reports and clinical trials focusing on
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ovarian transposition in the context of cancer and cross-referencing to eliminate
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duplication.
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TABULATION, INTEGRATION, AND RESULTS: Data were obtained using standard
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abstract templates to summarize study findings. Given the under-utilization of this
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procedure, we report available data with respect to indications, most commonly
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reported surgical techniques, reported complications associated with the procedure,
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and outcomes in the context of fertility and ovarian function. Women under the age
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of 40 with pelvic cancer requiring chemoradiotherapy are candidates for ovarian
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transposition, provided gonadotoxic chemotherapy is not required. Removing the
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ovaries out of the field of radiation increases the odds of maintaining ovarian
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function and becoming pregnant, spontaneously, through IVF or via surrogacy, in
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the future.
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CONCLUSION: Ovarian transposition is a safe but under-utilized procedure in the
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preservation of fertility and ovarian function in women with pelvic cancer.
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Physicians should consider and offer ovarian transposition in addition to other
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preservation methods as an Oncofertility option for these women.
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Introduction The American Cancer Society estimates that there are more than 15.5 million
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Americans with a history of cancer living in the US, and this number is expected to
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exceed 20 million over the next decade. Two of the most prevalent cancers in
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women are uterine (757,000), and colorectal (727,000) cancers 1. Increasing
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numbers of cancer survivors are confronted with morbidity secondary to exposure
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to chemotherapy and radiation treatments. For reproductive-aged women, the
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reserve of primordial follicles in the ovary is fixed and declines with age at a fairly
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predictable rate (Figure 1) 2. Thus, any injury to the ovaries reduces this pool and
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accelerates a woman’s reproductive aging.
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The American Society of Clinical Oncology (ASCO) and the National Comprehensive
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Cancer Network (NCCN) recommend offering ovarian transposition as an option for
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optimizing fertility preservation in patients with cancer3,4. Preserving ovarian
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function by sparing the ovaries from the direct deleterious effects of radiation can
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be accomplished with this procedure, which repositions the ovaries out of the field
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of radiation. The procedure is indicated for women of reproductive age who are
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undergoing pelvic or lower abdominal radiation therapy 5. Recently, less invasive
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laparoscopic and robotic approaches to ovarian transposition have been
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successfully performed and described.
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Sources We conducted an electronic search of all research articles published in
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English without time restriction, using PubMed and Cochrane databases for studies
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of ovarian transposition. The text words used in the search included “ovarian
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transposition,” “ovariopexy,” and “oophoropexy.” References from articles were
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reviewed and pertinent articles and reviews were used for the discussion.
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Study Selection
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The authors identified the appropriate articles for review. Of the 79 studies initially identified, 55 were selected after limiting the review to clinical trials and
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case reports focusing on ovarian transposition in the context of cancer. 24 articles
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focusing on endometriosis and adnexal torsion were excluded. Given the rarity of
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ovarian transposition and the scarcity of data available from large, prospective,
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randomized trials, selection of studies was not limited by the design or the number
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of patients in the studies. We report the available data and describe the indications
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for ovarian transposition, the most commonly reported surgical techniques, the
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potential complications associated with this procedure, and prognoses and
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outcomes in the context of ovarian function and fertility preservation for patients
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who have the procedure done prior to undergoing pelvic radiation and
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chemotherapy.
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Results
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Indications for ovarian transposition
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Female patients with gynecologic cancers, including cervical cancer, vaginal cancer, uterine cancer, and ovarian dysgerminomas, are candidates for ovarian
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transposition6. Ovarian transposition has also been utilized in non-gynecologic
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cancers of the pelvis including osteosarcoma, rhabdomyosarcoma, Hodgkin’s
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lymphoma, anorectal carcinomas, and medulloblastoma prior to radiation therapy7-
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literature. Women older than 40 years of age already have decreased ovarian
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reserve and are at higher risk for ovarian failure even with ovarian transposition 14.
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Menopausal women and women at risk of developing ovarian metastases are
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inappropriate candidates for ovarian transposition. Additionally, women who will
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be receiving chemotherapeutic agents with a low probability of gonadotoxicity are
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Cases of patients ranging from age 11 to age 40 have been reported in the
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candidates for the procedure. At gonadotoxic levels, systemic chemotherapy is
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deleterious to the ovaries, regardless of the anatomic location.
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Surgical techniques
Two surgical techniques for laparoscopic ovarian transposition have been
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described in the literature: lateral and medial approaches. The uterus can be used as
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a shield from radiation in certain cancers like Hodgkin’s lymphoma. For these
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patients, medial ovarian transposition has been described 15-18. However, in a study
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comparing medial and lateral ovarian transposition in patients receiving pelvic
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irradiation for Hodgkin’s disease, lateral ovarian transposition resulted in better
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outcomes 19. Seventeen patients of childbearing age received total lymphoid
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irradiation including pelvic and inguinal nodes. 15/17 patients underwent
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prophylactic bilateral oophoropexy during staging laparotomy: ten underwent
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lateral transposition and five had midline fixation. The patients were followed for
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reproductive and ovarian function by menstrual history and serum hormonal assays
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ACCEPTED MANUSCRIPT Moawad 7 for a minimum of 3 years. In 13 patients who remained in complete remission,
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normal cyclic ovarian activity was found in seven out of nine patients following
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lateral transposition (including one pregnancy), but only in one out of four cases
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after medial transposition. The authors concluded that lateral transposition should
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be preferred if ovarian protection is required prior to pelvic radiation19.
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Descriptions of the laparoscopic technique and variations using the lateral
approach have been reported in the literature20-22. A video depicting the technique
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is also available for viewing23. The procedure is performed under general anesthesia
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with the patient in the Trendelenburg position. Due to the final destination of the
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transposed ovaries outside of the pelvic cavity, consideration should be given to
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higher trocar placement than what is commonly used in pelvic laparoscopy. The
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location of the midline incision for the optical trocar varies in the literature, with
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some articles reporting the incision 5 cm above the umbilicus and others reporting
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the Lee-Huang point, located 3-4 cm above the umbilical line at the midpoint
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between the umbilicus and the xyphoid process (Figure 2)21. A Veress needle is then
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inserted at the umbilicus for insufflation with carbon dioxide to achieve adequate
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pneumoperitoneum and the primary trocar is then inserted at the umbilicus,
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followed by the optical trocar at a more cephalad location.
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Alternatively, open (Hasson) entry at the umbilicus can be performed,
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followed by the sub-xiphoid trocar insertion under laparoscopic guidance. The
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endoscopic camera is introduced through the sub-xiphoid port. A secondary trocar
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is placed in the midline at the umbilicus, in lieu of a supra-pubic trocar, due to the
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higher region for operating outside of the pelvis, and two secondary trocars are
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than the typical lower quadrant trocar insertion for other gynecologic procedures. If
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a midline approach is chosen as described above, the surgeon and the assistant will
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be facing the pelvis during the procedure, with a monitor at the foot of the operating
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table. Alternatively, 2 ipsilateral ports can be used instead of the midline approach,
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with the surgeon looking at a monitor across the operating table. The authors prefer
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the use of mini-laparoscopic instruments and trocars (3 mm) to facilitate healing.
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After inspecting the abdominal and pelvic anatomy, each utero-ovarian ligament is coagulated and transected to provide mobility to the ovary. The use of a
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vessel sealing cutting device may facilitate the procedure. The mesosalpinx and
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mesovarium are dissected (Figure 3). Each ovary is then mobilized with its
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corresponding blood supply in the infundibulopelvic ligament attached and
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transposed to the anterolateral abdominal wall. Care is taken to incise the
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peritoneum outside of the mesosalpingeal vessels to avoid compromising the blood
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supply to the transposed ovaries. The peritoneum is incised alongside the
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infundibulopelvic ligament, with careful attention to the ureter medially, to allow for
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complete mobilization of the ovary. The fallopian tubes can be left intact in an
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attempt to allow for future spontaneous conception24,25. Other reports describe
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either removing the fallopian tubes during the procedure, or transecting them and
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leaving them attached to the transposed ovaries21,24-26. Care is taken to adequately
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skeletonize the ovarian vessels to avoid kinking when the ovaries are pulled
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cephalad. The ovaries are then sutured securely at 2-3 points, using permanent
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sutures, to the transversalis fascia of the abdominal wall or the lower paracolic
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gutters (Figure 4). Surgical clips are placed at the border of each ovary for
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identification during radiation therapy planning and administration (Figures 5 and
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6)23. Transposition of the ovaries greater than 1.5 cm above the iliac crest is
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associated with a higher chance of preservation of ovarian function after pelvic
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radiotherapy27. Mobilizing the large bowel medially may provide more space for
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higher transposition when needed in cases requiring iliac lymph node irradiation.
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A few case reports detailing the medial approach technique have also been published. In this procedure, the utero-ovarian ligaments are coagulated and
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transected, as is done with the lateral approach. The ovaries are then fixed to their
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respective uterosacral ligaments behind the uterus and—as with the lateral
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approach—surgical clips are placed to mark the ovaries for identification during
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radiation treatment15,16.
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Variations to the described techniques have been reported in the literature. These include a surgical glove-single port technique and robotic-assisted ovarian
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transposition28-30. Yet another technique utilizes a percutaneous needle to transpose
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the ovaries; this procedure can be performed in the outpatient setting. A
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prospective study using percutaneous needle fixation demonstrated normal ovarian
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function in 11 of 12 patients diagnosed with either rectal cancer or Hodgkin’s
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lymphoma31. The study, however, did not report the exact time of follow-up when
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ovarian function was assessed.
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Various reports describe different strategies to manage the fallopian tubes at
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the time of ovarian transposition. Bilateral salpingectomy has been performed at the
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tube metastasis21,26. Sicam and colleagues reported completing ovarian
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transposition and bilateral salpingectomy on a 40-year-old woman diagnosed with
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stage IIB cervical carcinoma who was found to have fallopian tube metastasis on
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histologic evaluation. The surgeons’ rationale for performing bilateral
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salpingectomy was to detect possible occult metastases within the fallopian tubes
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and to reduce the risk of hydrosalpinx secondary to postoperative adhesions26. In
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their retrospective study, Huang and colleagues also performed bilateral
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salpingectomies on 14 patients for the latter reason21.
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In cases where the fallopian tubes have been left intact during ovarian transposition,
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reports of spontaneous intrauterine pregnancies have been described 24,25. No data
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is available regarding the risk of ectopic pregnancy after the preserved fallopian
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tubes have been exposed to radiation.
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Ovarian function following ovarian transposition
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Multiple small studies have reported successful ovarian function preservation following ovarian transposition and chemoradiotherapy. In a study by
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Huang and colleagues, only one of the seven patients younger than 39 years of age
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developed ovarian failure as evidenced by elevated FSH levels, with a mean follow-
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up period of 72 months after receiving concurrent chemoradiation32. Moreover, one
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meta-analysis calculated that ovarian transposition was associated with
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preservation of ovarian function in 90 percent of patients6. This was based on a
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number of subjective and objective data reported in the studies, including clinical
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symptoms, FSH, LH, and progesterone levels.
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The rates of ovarian function preservation differ based on the type of cancer treatment the patient receives. In a prospective study of 107 patients with cervical
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cancer, 104 patients underwent bilateral ovarian transposition prior to surgery,
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vaginal brachytherapy and/or external radiation therapy. The rates of ovarian
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function preservation differed depending on the type of radiotherapy; 90 percent of
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patients who underwent vaginal brachytherapy and 60 percent of patients who
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underwent external radiation therapy with vaginal brachytherapy had preserved
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ovarian function33.
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Fertility preservation following ovarian transposition
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Reproductive success following ovarian transposition has been reported in the literature34. A recent study reported 14 pregnancies (11 births and three
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miscarriages) following ovarian transposition in 11 women treated for Hodgkin’s
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lymphoma during a median follow-up period of 14 years25.
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In patients with preserved ovarian function following ovarian transposition, ovulation induction and oocyte retrieval have been successfully performed trans-
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abdominally from the transposed ovaries35,36. Successful surrogate pregnancies
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have been reported using oocytes retrieved from patients after ovarian
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transposition and cancer treatment with radiation and/or chemotherapy37-40.
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Two case reports described a combined approach using cryopreservation and
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ovarian transposition to ensure reproductive success in the future10,41. The main
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advantage of embryo and oocyte cryopreservation is the proven ability to preserve
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fertility in the future if the patient becomes infertile or sterile. Both may remain
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frozen indefinitely. The disadvantages include the cost (not commonly covered by
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stimulation that theoretically could affect prognosis, and the need for the egg
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retrieval procedure. It is important to note that ovarian tissue cryopreservation
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remains experimental at this time and its availability and cost vary widely
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depending on the institution.
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Complications of ovarian transposition
Few complications of ovarian transposition have been reported. Rodriguez
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and colleagues reported two cases of ovarian torsion after laparoscopic ovarian
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transposition. Absorbable sutures were used in these two cases42. Ovarian
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contamination by cancer cells is possible, especially when the primary cancer is
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likely to extend into gonadal tissue43,44. Picone and colleagues reported abdominal
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wall metastasis at the trocar site following ovarian transposition45. A prospective
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study reported the development of benign ovarian cysts requiring oophorectomy in
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two patients who underwent ovarian transposition and pelvic radiation for cervical
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cancer46. Furthermore, Morice and colleagues reported two cases of ovarian
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metastasis three years after the end of treatment for Stage IB squamous cell cervical
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carcinoma47.
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In addition to these reported complications and outcomes, there is also the
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risk of chronic pelvic or abdominal pain and Mittelschmerz pain and a risk of injury
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to the ovarian vessels during the procedure, which can compromise ovarian
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function. Torsion of the vascular pedicle can also compromise blood supply, but the
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risk is decreased if the ovary is fixed firmly in its final extra-pelvic position in at
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least 2-3 points48. It is important to consider and counsel the patient appropriately
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anesthesia, bleeding, transfusion, injury to the bowel or the ureters, infection,
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venous thromboembolism and the risk of reoperation.
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Discussion
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Radiation and chemotherapy can both reduce ovarian function, leading to
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infertility and premature ovarian failure. Premature menopause with long-term
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estrogen deprivation can lead to osteopenia and osteoporosis. Certain
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chemotherapy drugs increase the loss of primordial follicles, thus accelerating the
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process of normal reproductive aging. The effect of chemotherapeutic drugs on
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ovarian function depends on the type and dose of agents used and the number of
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treatment cycles. Additionally, the incidence of acute ovarian failure, infertility, and
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early menopause from chemotherapy correlates with the woman’s age49.
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Cyclophosphamide and other alkylating agents such as busulfan, chlorambucil,
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procarbazine, ifosfamide; some nonclassical alkylators such as dacarbazine and
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temozolomide; and heavy metals such as carboplatin and cisplatin are the most
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toxic to the ovaries50,51. When exposed to these chemotherapeutic medications,
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ovarian insufficiency can be transient or permanent. In children, ovarian
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insufficiency can lead to pubertal delay. The incidence of premature menopause in
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survivors of childhood cancers can reach up to 30 percent52. In older women, this
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can lead to low estradiol levels, oligomenorrhea, amenorrhea, impaired fertility or
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ultimately, premature ovarian failure. Women not receiving sterilizing doses of
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radiation therapy or chemotherapy may be able to conceive post-treatment, but
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they may be at increased risk of suffering complications during pregnancy53.
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Radiation therapy is an integral component in the management of several pelvic malignancies including cancers of the cervix, endometrium, rectum, and
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bladder, as well as lymphomas that involve the pelvic region. Doses required for the
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management of these various malignancies can range from a minimum of 30
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Gray(Gy) in divided doses for lymphoma to as high as 60 Gy or greater for locally
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advanced cervical carcinomas. The ovaries are exquisitely radiosensitive and doses
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as low as 10 Gy can be associated with a high risk of ovarian failure.
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Natural atresia of ovarian primordial follicles begins at birth in a predictable manner (Figure 1). Ionizing radiation can hasten this decline through direct DNA
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damage to ovarian follicles, leading to follicular atrophy and decreased ovarian
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follicular reserve. The amount of damage to the ovaries is dependent on the type of
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agent, the doses of radiation the patient is exposed to, the age of the patient at the
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time of radiation exposure, and the extent of the radiation treatment field54,55.
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Mathematical models have been devised to estimate the dose required to induce
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ovarian failure. Wallace and colleagues extended that model to account for age at
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onset of radiation treatment (Figure 7). Their model uses the Effective Sterilizing
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Dose (ESD), which is defined as the dose of fractionated radiotherapy at which
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ovarian failure occurs in 97.5 percent of patients54,56. The ESD decreases with
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increasing age at treatment: at birth, ESD is 20.3 Gy; at 10 years, 18.4 Gy; at 20
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years, 16.5 Gy; and at 30 years, 14.3 Gy. Figure 7 graphically depicts the risk of
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developing acute ovarian failure, defined as failure within 5 years of diagnosis,
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stratified by age and radiation dose to the ovary.
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The combined effects of radiation therapy to the pelvis along with systemic chemotherapy are more damaging to the ovaries than one or the other alone. In a
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retrospective study of 162 premenopausal women with colon or rectal cancer who
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underwent adjuvant chemotherapy and chemoradiotherapy, more than 90 percent
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of patients with rectal cancer experienced long-term amenorrhea57. By itself, pelvic
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irradiation results in follicular loss, impaired follicular maturation, and cortical and
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capsular damage58. Abdominopelvic irradiation can lead to high rates of premature
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ovarian failure, with even less than 2 Gy causing the loss of 50 percent of primordial
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follicles. Pelvic irradiation may also impair the uterus leading to poor pregnancy
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outcomes. The pathophysiology seems to involve vascular, endometrial, and
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myometrial damage59,60. In some cases, the only option to achieve a successful
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pregnancy may be with the use of a gestational surrogate, donor eggs, or both. The decision to undergo ovarian transposition for fertility preservation depends
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on each patient’s clinical scenario and personal preferences. ASCO, the American
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Society of Reproductive Medicine (ASRM), and the American Academy of Pediatrics
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(AAP) have guidelines regarding the options and recommendations for fertility
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preservation for women61-63. The options include embryo/oocyte cryopreservation,
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ovarian transposition, ovarian tissue freezing with re-transplantation
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(experimental), and the use of Gonadotropin-Releasing Hormone (GnRH) agonists64.
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The woman’s current state of health should be considered, as some women with
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severely debilitating cancers may be too ill to undergo any fertility preservation
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procedure55.
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Research indicates that many patients with a cancer diagnosis do not receive adequate information regarding fertility preservation. Less than half of cancer
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patients are referred to a reproductive specialist65-67. Despite the ASCO, AAP, and
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ASRM guidelines and recommendations, a study reported that only 18 percent of
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oncologists had any patient resources on fertility preservation available and only 50
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percent reported moderate to high confidence in knowledge regarding the subject68.
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Many barriers have been identified, including a lack of physician knowledge about
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fertility preservation options and resources; time constraints associated with
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assisted reproductive technologies and delaying the initiation of cancer therapy;
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and cost concerns and patient prognosis, especially with advanced disease. Women
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with cancer are interested in discussing fertility preservation and their cancer care
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providers should address the possibility of infertility as soon as possible before the
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initiation of treatment69. The discussion will reduce stress and can improve patient
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satisfaction and the woman’s quality of life in the long run70. Collaborative care
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between the oncology team, infertility specialists, psychologists, the patient and her
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family can help ensure these women have access to such information and services. It
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is imperative to remember that for adult survivors, their cancer treatment is a
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distant memory, but the issue of infertility remains a present problem that limits
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their social lives and curtails their hope of a biologic family71.
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The lack of well-designed clinical trials limits the quality of available data on
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the outcomes of ovarian transposition. Other limitations in reviewing the outcomes
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of ovarian transposition are the lack of comparative data regarding the different
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types of radiotherapy, the different chemotherapeutic agents used in the literature,
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understanding of these limitations, the authors endeavored to review the available
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literature and to synthesize this concise summary for the gynecologic surgeon to
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adequately counsel affected patients, to maximize the utilization of fertility
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preservation options including ovarian transposition, to minimize the long term
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impact of cancer on the patient’s future, and to improve quality of life.
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Conclusions
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Laparoscopic ovarian transposition is a feasible, safe procedure and is recommended by ASCO and NCCN as an option for optimizing fertility preservation.
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The procedure increases the odds of maintaining ovarian function and as such,
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should be offered to women of reproductive age along with the other options
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available for fertility preservation. The under-utilization and the limited studies on
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laparoscopic ovarian transposition mandate the need for prospective randomized
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trials to better inform cancer treatment so that maintaining ovarian function after
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cancer cure is optimized.
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Figure 1. The reserve of primordial follicles in the ovary is fixed and declines with age at a fairly predictable rate (Graph obtained from Reference 2; permission from
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Thieme on file).
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Fig 2: Trocar placement strategy. O: Final destination of the ovaries; A: Sub-xiphoid optical trocar site (Lee-Huang point); U: Umbilicus; B: Accessory trocar sites.
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Graph reprinted from Reference 33, with permission from Elsevier (on file)
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Figure 3. The mesosalpinx and mesovarium are dissected and the ovary is
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mobilized to the anterolateral abdominal wall.
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Figure 4. Once an adequate length of the infundibulopelvic ligament is skeletonized, the ovary is sutured to the transversalis fascia using permanent sutures at 2-3 points to prevent ovarian torsion. Vascular clips are applied to the sutures as
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markers for radiation simulation.
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Figure 5. The transpositioned ovaries (yellow) at their final location of L3- L4 upon radiation simulation.
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Figure 6. Radiation simulation showing the transpositioned ovaries (yellow) and their optimal location in relationship to the planned radiation field.
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Figure 7. The risk of developing AOF increases with increasing radiation doses to
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the ovaries (Graph obtained from Reference 56; permission from Elsevier on file).
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S1553-4650(16)31038-X
DOI:
10.1016/j.jmig.2016.08.831
Reference:
JMIG 2943
To appear in:
The Journal of Minimally Invasive Gynecology
Received Date: 1 July 2016 Revised Date:
24 August 2016
Accepted Date: 27 August 2016
Please cite this article as: Moawad NS, Santamaria E, Rhoton-Vlasak A, Lightsey JL, Laparoscopic Ovarian Transposition Before Pelvic Cancer Treatment: Ovarian Function and Fertility Preservation, The Journal of Minimally Invasive Gynecology (2016), doi: 10.1016/j.jmig.2016.08.831. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Moawad 1 Laparoscopic Ovarian Transposition Before Pelvic Cancer Treatment: Ovarian Function and Fertility Preservation Nash S. Moawad, M.D., M.S.1; Estefania Santamaria, B.S.2; Alice Rhoton-Vlasak, M.D.3; Judith L. Lightsey, M.D.4
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Associate Professor Minimally-Invasive Gynecologic Surgery
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Department of Obstetrics and Gynecology
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University of Florida College of Medicine
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P.O. Box 100294
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Gainesville, FL 32610
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Office: 352-273-7660 Fax: 352-392-3498
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[email protected]
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Corresponding Author: Nash S. Moawad, MD, MS, FACOG
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Disclosure: The authors report no financial disclosures or conflict or interest related
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to this study. 1. 2. 3. 4.
Section of Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, University of Florida College of Medicine University of Florida College of Medicine Division of Reproductive Endocrinology & Infertility, Department of Obstetrics and Gynecology, University of Florida College of Medicine Department of Radiation Oncology, University of Florida College of Medicine
ACCEPTED MANUSCRIPT Moawad 2 Precis: We describe ovarian transposition—an underused procedure in young
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women diagnosed with pelvic cancers—its indications, technique and outcomes in
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the context of ovarian function and fertility preservation following
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chemoradiotherapy.
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ACCEPTED MANUSCRIPT Moawad 3 Abstract
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OBJECTIVE: To summarize available studies with respect to indications for ovarian
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transposition and patient outcomes post-procedure in the context of ovarian
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function and fertility preservation following radiation and chemotherapy.
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DATA SOURCES: We conducted an electronic search of research articles published
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in English without date restriction using PubMed and Cochrane databases.
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METHODS OF STUDY SELECTION: Of the 79 studies initially identified, 55 were
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selected after limiting the review to those case reports and clinical trials focusing on
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ovarian transposition in the context of cancer and cross-referencing to eliminate
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duplication.
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TABULATION, INTEGRATION, AND RESULTS: Data were obtained using standard
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abstract templates to summarize study findings. Given the under-utilization of this
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procedure, we report available data with respect to indications, most commonly
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reported surgical techniques, reported complications associated with the procedure,
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and outcomes in the context of fertility and ovarian function. Women under the age
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of 40 with pelvic cancer requiring chemoradiotherapy are candidates for ovarian
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transposition, provided gonadotoxic chemotherapy is not required. Removing the
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ovaries out of the field of radiation increases the odds of maintaining ovarian
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function and becoming pregnant, spontaneously, through IVF or via surrogacy, in
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the future.
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CONCLUSION: Ovarian transposition is a safe but under-utilized procedure in the
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preservation of fertility and ovarian function in women with pelvic cancer.
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Physicians should consider and offer ovarian transposition in addition to other
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preservation methods as an Oncofertility option for these women.
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Introduction The American Cancer Society estimates that there are more than 15.5 million
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Americans with a history of cancer living in the US, and this number is expected to
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exceed 20 million over the next decade. Two of the most prevalent cancers in
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women are uterine (757,000), and colorectal (727,000) cancers 1. Increasing
8
numbers of cancer survivors are confronted with morbidity secondary to exposure
9
to chemotherapy and radiation treatments. For reproductive-aged women, the
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reserve of primordial follicles in the ovary is fixed and declines with age at a fairly
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predictable rate (Figure 1) 2. Thus, any injury to the ovaries reduces this pool and
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accelerates a woman’s reproductive aging.
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The American Society of Clinical Oncology (ASCO) and the National Comprehensive
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Cancer Network (NCCN) recommend offering ovarian transposition as an option for
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optimizing fertility preservation in patients with cancer3,4. Preserving ovarian
16
function by sparing the ovaries from the direct deleterious effects of radiation can
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be accomplished with this procedure, which repositions the ovaries out of the field
18
of radiation. The procedure is indicated for women of reproductive age who are
19
undergoing pelvic or lower abdominal radiation therapy 5. Recently, less invasive
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laparoscopic and robotic approaches to ovarian transposition have been
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successfully performed and described.
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Sources We conducted an electronic search of all research articles published in
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English without time restriction, using PubMed and Cochrane databases for studies
4
of ovarian transposition. The text words used in the search included “ovarian
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transposition,” “ovariopexy,” and “oophoropexy.” References from articles were
6
reviewed and pertinent articles and reviews were used for the discussion.
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Study Selection
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The authors identified the appropriate articles for review. Of the 79 studies initially identified, 55 were selected after limiting the review to clinical trials and
10
case reports focusing on ovarian transposition in the context of cancer. 24 articles
11
focusing on endometriosis and adnexal torsion were excluded. Given the rarity of
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ovarian transposition and the scarcity of data available from large, prospective,
13
randomized trials, selection of studies was not limited by the design or the number
14
of patients in the studies. We report the available data and describe the indications
15
for ovarian transposition, the most commonly reported surgical techniques, the
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potential complications associated with this procedure, and prognoses and
17
outcomes in the context of ovarian function and fertility preservation for patients
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who have the procedure done prior to undergoing pelvic radiation and
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chemotherapy.
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Results
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Indications for ovarian transposition
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Female patients with gynecologic cancers, including cervical cancer, vaginal cancer, uterine cancer, and ovarian dysgerminomas, are candidates for ovarian
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transposition6. Ovarian transposition has also been utilized in non-gynecologic
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cancers of the pelvis including osteosarcoma, rhabdomyosarcoma, Hodgkin’s
3
lymphoma, anorectal carcinomas, and medulloblastoma prior to radiation therapy7-
4
13.
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literature. Women older than 40 years of age already have decreased ovarian
6
reserve and are at higher risk for ovarian failure even with ovarian transposition 14.
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Menopausal women and women at risk of developing ovarian metastases are
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inappropriate candidates for ovarian transposition. Additionally, women who will
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be receiving chemotherapeutic agents with a low probability of gonadotoxicity are
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Cases of patients ranging from age 11 to age 40 have been reported in the
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candidates for the procedure. At gonadotoxic levels, systemic chemotherapy is
11
deleterious to the ovaries, regardless of the anatomic location.
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Surgical techniques
Two surgical techniques for laparoscopic ovarian transposition have been
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described in the literature: lateral and medial approaches. The uterus can be used as
15
a shield from radiation in certain cancers like Hodgkin’s lymphoma. For these
16
patients, medial ovarian transposition has been described 15-18. However, in a study
17
comparing medial and lateral ovarian transposition in patients receiving pelvic
18
irradiation for Hodgkin’s disease, lateral ovarian transposition resulted in better
19
outcomes 19. Seventeen patients of childbearing age received total lymphoid
20
irradiation including pelvic and inguinal nodes. 15/17 patients underwent
21
prophylactic bilateral oophoropexy during staging laparotomy: ten underwent
22
lateral transposition and five had midline fixation. The patients were followed for
23
reproductive and ovarian function by menstrual history and serum hormonal assays
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ACCEPTED MANUSCRIPT Moawad 7 for a minimum of 3 years. In 13 patients who remained in complete remission,
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normal cyclic ovarian activity was found in seven out of nine patients following
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lateral transposition (including one pregnancy), but only in one out of four cases
4
after medial transposition. The authors concluded that lateral transposition should
5
be preferred if ovarian protection is required prior to pelvic radiation19.
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Descriptions of the laparoscopic technique and variations using the lateral
approach have been reported in the literature20-22. A video depicting the technique
8
is also available for viewing23. The procedure is performed under general anesthesia
9
with the patient in the Trendelenburg position. Due to the final destination of the
10
transposed ovaries outside of the pelvic cavity, consideration should be given to
11
higher trocar placement than what is commonly used in pelvic laparoscopy. The
12
location of the midline incision for the optical trocar varies in the literature, with
13
some articles reporting the incision 5 cm above the umbilicus and others reporting
14
the Lee-Huang point, located 3-4 cm above the umbilical line at the midpoint
15
between the umbilicus and the xyphoid process (Figure 2)21. A Veress needle is then
16
inserted at the umbilicus for insufflation with carbon dioxide to achieve adequate
17
pneumoperitoneum and the primary trocar is then inserted at the umbilicus,
18
followed by the optical trocar at a more cephalad location.
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Alternatively, open (Hasson) entry at the umbilicus can be performed,
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followed by the sub-xiphoid trocar insertion under laparoscopic guidance. The
21
endoscopic camera is introduced through the sub-xiphoid port. A secondary trocar
22
is placed in the midline at the umbilicus, in lieu of a supra-pubic trocar, due to the
23
higher region for operating outside of the pelvis, and two secondary trocars are
ACCEPTED MANUSCRIPT Moawad 8 placed in the paramedian lines at the same level of the umbilicus, which is higher
2
than the typical lower quadrant trocar insertion for other gynecologic procedures. If
3
a midline approach is chosen as described above, the surgeon and the assistant will
4
be facing the pelvis during the procedure, with a monitor at the foot of the operating
5
table. Alternatively, 2 ipsilateral ports can be used instead of the midline approach,
6
with the surgeon looking at a monitor across the operating table. The authors prefer
7
the use of mini-laparoscopic instruments and trocars (3 mm) to facilitate healing.
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After inspecting the abdominal and pelvic anatomy, each utero-ovarian ligament is coagulated and transected to provide mobility to the ovary. The use of a
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vessel sealing cutting device may facilitate the procedure. The mesosalpinx and
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mesovarium are dissected (Figure 3). Each ovary is then mobilized with its
12
corresponding blood supply in the infundibulopelvic ligament attached and
13
transposed to the anterolateral abdominal wall. Care is taken to incise the
14
peritoneum outside of the mesosalpingeal vessels to avoid compromising the blood
15
supply to the transposed ovaries. The peritoneum is incised alongside the
16
infundibulopelvic ligament, with careful attention to the ureter medially, to allow for
17
complete mobilization of the ovary. The fallopian tubes can be left intact in an
18
attempt to allow for future spontaneous conception24,25. Other reports describe
19
either removing the fallopian tubes during the procedure, or transecting them and
20
leaving them attached to the transposed ovaries21,24-26. Care is taken to adequately
21
skeletonize the ovarian vessels to avoid kinking when the ovaries are pulled
22
cephalad. The ovaries are then sutured securely at 2-3 points, using permanent
23
sutures, to the transversalis fascia of the abdominal wall or the lower paracolic
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gutters (Figure 4). Surgical clips are placed at the border of each ovary for
2
identification during radiation therapy planning and administration (Figures 5 and
3
6)23. Transposition of the ovaries greater than 1.5 cm above the iliac crest is
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associated with a higher chance of preservation of ovarian function after pelvic
6
radiotherapy27. Mobilizing the large bowel medially may provide more space for
7
higher transposition when needed in cases requiring iliac lymph node irradiation.
8
A few case reports detailing the medial approach technique have also been published. In this procedure, the utero-ovarian ligaments are coagulated and
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transected, as is done with the lateral approach. The ovaries are then fixed to their
11
respective uterosacral ligaments behind the uterus and—as with the lateral
12
approach—surgical clips are placed to mark the ovaries for identification during
13
radiation treatment15,16.
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Variations to the described techniques have been reported in the literature. These include a surgical glove-single port technique and robotic-assisted ovarian
16
transposition28-30. Yet another technique utilizes a percutaneous needle to transpose
17
the ovaries; this procedure can be performed in the outpatient setting. A
18
prospective study using percutaneous needle fixation demonstrated normal ovarian
19
function in 11 of 12 patients diagnosed with either rectal cancer or Hodgkin’s
20
lymphoma31. The study, however, did not report the exact time of follow-up when
21
ovarian function was assessed.
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22
Various reports describe different strategies to manage the fallopian tubes at
23
the time of ovarian transposition. Bilateral salpingectomy has been performed at the
ACCEPTED MANUSCRIPT Moawad 10 time of ovarian transposition in several reports in order to evaluate for fallopian
2
tube metastasis21,26. Sicam and colleagues reported completing ovarian
3
transposition and bilateral salpingectomy on a 40-year-old woman diagnosed with
4
stage IIB cervical carcinoma who was found to have fallopian tube metastasis on
5
histologic evaluation. The surgeons’ rationale for performing bilateral
6
salpingectomy was to detect possible occult metastases within the fallopian tubes
7
and to reduce the risk of hydrosalpinx secondary to postoperative adhesions26. In
8
their retrospective study, Huang and colleagues also performed bilateral
9
salpingectomies on 14 patients for the latter reason21.
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In cases where the fallopian tubes have been left intact during ovarian transposition,
11
reports of spontaneous intrauterine pregnancies have been described 24,25. No data
12
is available regarding the risk of ectopic pregnancy after the preserved fallopian
13
tubes have been exposed to radiation.
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Ovarian function following ovarian transposition
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Multiple small studies have reported successful ovarian function preservation following ovarian transposition and chemoradiotherapy. In a study by
17
Huang and colleagues, only one of the seven patients younger than 39 years of age
18
developed ovarian failure as evidenced by elevated FSH levels, with a mean follow-
19
up period of 72 months after receiving concurrent chemoradiation32. Moreover, one
20
meta-analysis calculated that ovarian transposition was associated with
21
preservation of ovarian function in 90 percent of patients6. This was based on a
22
number of subjective and objective data reported in the studies, including clinical
23
symptoms, FSH, LH, and progesterone levels.
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The rates of ovarian function preservation differ based on the type of cancer treatment the patient receives. In a prospective study of 107 patients with cervical
3
cancer, 104 patients underwent bilateral ovarian transposition prior to surgery,
4
vaginal brachytherapy and/or external radiation therapy. The rates of ovarian
5
function preservation differed depending on the type of radiotherapy; 90 percent of
6
patients who underwent vaginal brachytherapy and 60 percent of patients who
7
underwent external radiation therapy with vaginal brachytherapy had preserved
8
ovarian function33.
9
Fertility preservation following ovarian transposition
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Reproductive success following ovarian transposition has been reported in the literature34. A recent study reported 14 pregnancies (11 births and three
12
miscarriages) following ovarian transposition in 11 women treated for Hodgkin’s
13
lymphoma during a median follow-up period of 14 years25.
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In patients with preserved ovarian function following ovarian transposition, ovulation induction and oocyte retrieval have been successfully performed trans-
16
abdominally from the transposed ovaries35,36. Successful surrogate pregnancies
17
have been reported using oocytes retrieved from patients after ovarian
18
transposition and cancer treatment with radiation and/or chemotherapy37-40.
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Two case reports described a combined approach using cryopreservation and
20
ovarian transposition to ensure reproductive success in the future10,41. The main
21
advantage of embryo and oocyte cryopreservation is the proven ability to preserve
22
fertility in the future if the patient becomes infertile or sterile. Both may remain
23
frozen indefinitely. The disadvantages include the cost (not commonly covered by
ACCEPTED MANUSCRIPT Moawad 12 insurance), the 2-3 week delay to begin cancer therapy, high estradiol levels during
2
stimulation that theoretically could affect prognosis, and the need for the egg
3
retrieval procedure. It is important to note that ovarian tissue cryopreservation
4
remains experimental at this time and its availability and cost vary widely
5
depending on the institution.
6
Complications of ovarian transposition
Few complications of ovarian transposition have been reported. Rodriguez
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and colleagues reported two cases of ovarian torsion after laparoscopic ovarian
9
transposition. Absorbable sutures were used in these two cases42. Ovarian
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contamination by cancer cells is possible, especially when the primary cancer is
11
likely to extend into gonadal tissue43,44. Picone and colleagues reported abdominal
12
wall metastasis at the trocar site following ovarian transposition45. A prospective
13
study reported the development of benign ovarian cysts requiring oophorectomy in
14
two patients who underwent ovarian transposition and pelvic radiation for cervical
15
cancer46. Furthermore, Morice and colleagues reported two cases of ovarian
16
metastasis three years after the end of treatment for Stage IB squamous cell cervical
17
carcinoma47.
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In addition to these reported complications and outcomes, there is also the
19
risk of chronic pelvic or abdominal pain and Mittelschmerz pain and a risk of injury
20
to the ovarian vessels during the procedure, which can compromise ovarian
21
function. Torsion of the vascular pedicle can also compromise blood supply, but the
22
risk is decreased if the ovary is fixed firmly in its final extra-pelvic position in at
23
least 2-3 points48. It is important to consider and counsel the patient appropriately
ACCEPTED MANUSCRIPT Moawad 13 regarding the general complications associated with surgery, such as the risk of
2
anesthesia, bleeding, transfusion, injury to the bowel or the ureters, infection,
3
venous thromboembolism and the risk of reoperation.
4
Discussion
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Radiation and chemotherapy can both reduce ovarian function, leading to
6
infertility and premature ovarian failure. Premature menopause with long-term
7
estrogen deprivation can lead to osteopenia and osteoporosis. Certain
8
chemotherapy drugs increase the loss of primordial follicles, thus accelerating the
9
process of normal reproductive aging. The effect of chemotherapeutic drugs on
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ovarian function depends on the type and dose of agents used and the number of
11
treatment cycles. Additionally, the incidence of acute ovarian failure, infertility, and
12
early menopause from chemotherapy correlates with the woman’s age49.
13
Cyclophosphamide and other alkylating agents such as busulfan, chlorambucil,
14
procarbazine, ifosfamide; some nonclassical alkylators such as dacarbazine and
15
temozolomide; and heavy metals such as carboplatin and cisplatin are the most
16
toxic to the ovaries50,51. When exposed to these chemotherapeutic medications,
17
ovarian insufficiency can be transient or permanent. In children, ovarian
18
insufficiency can lead to pubertal delay. The incidence of premature menopause in
19
survivors of childhood cancers can reach up to 30 percent52. In older women, this
20
can lead to low estradiol levels, oligomenorrhea, amenorrhea, impaired fertility or
21
ultimately, premature ovarian failure. Women not receiving sterilizing doses of
22
radiation therapy or chemotherapy may be able to conceive post-treatment, but
23
they may be at increased risk of suffering complications during pregnancy53.
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Radiation therapy is an integral component in the management of several pelvic malignancies including cancers of the cervix, endometrium, rectum, and
3
bladder, as well as lymphomas that involve the pelvic region. Doses required for the
4
management of these various malignancies can range from a minimum of 30
5
Gray(Gy) in divided doses for lymphoma to as high as 60 Gy or greater for locally
6
advanced cervical carcinomas. The ovaries are exquisitely radiosensitive and doses
7
as low as 10 Gy can be associated with a high risk of ovarian failure.
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Natural atresia of ovarian primordial follicles begins at birth in a predictable manner (Figure 1). Ionizing radiation can hasten this decline through direct DNA
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damage to ovarian follicles, leading to follicular atrophy and decreased ovarian
11
follicular reserve. The amount of damage to the ovaries is dependent on the type of
12
agent, the doses of radiation the patient is exposed to, the age of the patient at the
13
time of radiation exposure, and the extent of the radiation treatment field54,55.
14
Mathematical models have been devised to estimate the dose required to induce
15
ovarian failure. Wallace and colleagues extended that model to account for age at
16
onset of radiation treatment (Figure 7). Their model uses the Effective Sterilizing
17
Dose (ESD), which is defined as the dose of fractionated radiotherapy at which
18
ovarian failure occurs in 97.5 percent of patients54,56. The ESD decreases with
19
increasing age at treatment: at birth, ESD is 20.3 Gy; at 10 years, 18.4 Gy; at 20
20
years, 16.5 Gy; and at 30 years, 14.3 Gy. Figure 7 graphically depicts the risk of
21
developing acute ovarian failure, defined as failure within 5 years of diagnosis,
22
stratified by age and radiation dose to the ovary.
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The combined effects of radiation therapy to the pelvis along with systemic chemotherapy are more damaging to the ovaries than one or the other alone. In a
3
retrospective study of 162 premenopausal women with colon or rectal cancer who
4
underwent adjuvant chemotherapy and chemoradiotherapy, more than 90 percent
5
of patients with rectal cancer experienced long-term amenorrhea57. By itself, pelvic
6
irradiation results in follicular loss, impaired follicular maturation, and cortical and
7
capsular damage58. Abdominopelvic irradiation can lead to high rates of premature
8
ovarian failure, with even less than 2 Gy causing the loss of 50 percent of primordial
9
follicles. Pelvic irradiation may also impair the uterus leading to poor pregnancy
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outcomes. The pathophysiology seems to involve vascular, endometrial, and
11
myometrial damage59,60. In some cases, the only option to achieve a successful
12
pregnancy may be with the use of a gestational surrogate, donor eggs, or both. The decision to undergo ovarian transposition for fertility preservation depends
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on each patient’s clinical scenario and personal preferences. ASCO, the American
15
Society of Reproductive Medicine (ASRM), and the American Academy of Pediatrics
16
(AAP) have guidelines regarding the options and recommendations for fertility
17
preservation for women61-63. The options include embryo/oocyte cryopreservation,
18
ovarian transposition, ovarian tissue freezing with re-transplantation
19
(experimental), and the use of Gonadotropin-Releasing Hormone (GnRH) agonists64.
20
The woman’s current state of health should be considered, as some women with
21
severely debilitating cancers may be too ill to undergo any fertility preservation
22
procedure55.
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Research indicates that many patients with a cancer diagnosis do not receive adequate information regarding fertility preservation. Less than half of cancer
3
patients are referred to a reproductive specialist65-67. Despite the ASCO, AAP, and
4
ASRM guidelines and recommendations, a study reported that only 18 percent of
5
oncologists had any patient resources on fertility preservation available and only 50
6
percent reported moderate to high confidence in knowledge regarding the subject68.
7
Many barriers have been identified, including a lack of physician knowledge about
8
fertility preservation options and resources; time constraints associated with
9
assisted reproductive technologies and delaying the initiation of cancer therapy;
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and cost concerns and patient prognosis, especially with advanced disease. Women
11
with cancer are interested in discussing fertility preservation and their cancer care
12
providers should address the possibility of infertility as soon as possible before the
13
initiation of treatment69. The discussion will reduce stress and can improve patient
14
satisfaction and the woman’s quality of life in the long run70. Collaborative care
15
between the oncology team, infertility specialists, psychologists, the patient and her
16
family can help ensure these women have access to such information and services. It
17
is imperative to remember that for adult survivors, their cancer treatment is a
18
distant memory, but the issue of infertility remains a present problem that limits
19
their social lives and curtails their hope of a biologic family71.
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The lack of well-designed clinical trials limits the quality of available data on
21
the outcomes of ovarian transposition. Other limitations in reviewing the outcomes
22
of ovarian transposition are the lack of comparative data regarding the different
23
types of radiotherapy, the different chemotherapeutic agents used in the literature,
ACCEPTED MANUSCRIPT Moawad 17 and the heterogeneity of the patient populations and the techniques used. With an
2
understanding of these limitations, the authors endeavored to review the available
3
literature and to synthesize this concise summary for the gynecologic surgeon to
4
adequately counsel affected patients, to maximize the utilization of fertility
5
preservation options including ovarian transposition, to minimize the long term
6
impact of cancer on the patient’s future, and to improve quality of life.
7
Conclusions
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Laparoscopic ovarian transposition is a feasible, safe procedure and is recommended by ASCO and NCCN as an option for optimizing fertility preservation.
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The procedure increases the odds of maintaining ovarian function and as such,
11
should be offered to women of reproductive age along with the other options
12
available for fertility preservation. The under-utilization and the limited studies on
13
laparoscopic ovarian transposition mandate the need for prospective randomized
14
trials to better inform cancer treatment so that maintaining ovarian function after
15
cancer cure is optimized.
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Figure 1. The reserve of primordial follicles in the ovary is fixed and declines with age at a fairly predictable rate (Graph obtained from Reference 2; permission from
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Thieme on file).
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Fig 2: Trocar placement strategy. O: Final destination of the ovaries; A: Sub-xiphoid optical trocar site (Lee-Huang point); U: Umbilicus; B: Accessory trocar sites.
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Graph reprinted from Reference 33, with permission from Elsevier (on file)
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Figure 3. The mesosalpinx and mesovarium are dissected and the ovary is
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mobilized to the anterolateral abdominal wall.
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Figure 4. Once an adequate length of the infundibulopelvic ligament is skeletonized, the ovary is sutured to the transversalis fascia using permanent sutures at 2-3 points to prevent ovarian torsion. Vascular clips are applied to the sutures as
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markers for radiation simulation.
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Figure 5. The transpositioned ovaries (yellow) at their final location of L3- L4 upon radiation simulation.
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Figure 6. Radiation simulation showing the transpositioned ovaries (yellow) and their optimal location in relationship to the planned radiation field.
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Figure 7. The risk of developing AOF increases with increasing radiation doses to
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the ovaries (Graph obtained from Reference 56; permission from Elsevier on file).
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