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Hum. Reprod. Advance Access originally published online on November 13, 2007
Human Reproduction 2008 23(1):117-121; doi:10.1093/humrep/dem368
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© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Laparoscopic oophoropexy prior to radiation for pediatric brain tumor and subsequent ovarian function*

Wendy Kuohung1,7, Katherine Ram2, Debbie M. Cheng3, Karen J. Marcus4, Lisa R. Diller5,6 and Marc R. Laufer1,2,8

1 Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA 2 Division of Gynecology, Children’s Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA 3 Department of Biostatistics, Boston University School of Public Health, 715 Albany Street, Boston, MA 02118, USA 4 Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute/Children’s Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA 5 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA 6 Department of Medicine, Children’s Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA 7 Present address: Department of Obstetrics and Gynecology, Boston University School of Medicine, 85 East Concord Street, Sixth Floor, Boston, MA 02118, USA

8 Correspondence address. Tel: +1-617-355-5785; Fax: +1-617-730-0186; E-mail: marc.laufer{at}childrens.harvard.edu (M.R.L.)


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
BACKGROUND: Ovarian failure has been reported to occur in female cancer survivors who had received spinal radiation as children. We aimed to determine whether laparoscopic unilateral oophoropexy prior to radiotherapy effectively preserves ovarian function.

METHODS: In a retrospective analysis, the study group comprised girls, aged 18 and younger, who received spinal irradiation for a brain tumor. Ovarian dysfunction, the primary endpoint, was defined as an elevated follicle-stimulating hormone level or persistent amenorrhea.

RESULTS: After applying exclusion criteria, 15 patients comprised the group that had undergone laparoscopic oophoropexy, and 11 patients comprised the comparison group that did not have oophoropexy. Mean age at diagnosis, length of follow-up, proportion of high-risk tumors and doses and duration of chemotherapy and radiation were not different between the two groups. Two of 15 patients (13%, 95% CI 0.2–40%) with oophoropexy had ovarian dysfunction compared with five of 11 (45%, 95% CI 17–77%) in the comparison group (P = 0.09).

CONCLUSIONS: Oophoropexy may protect against radiation-induced ovarian failure in girls receiving spinal radiation. A high risk of ovarian dysfunction was seen in patients who did not undergo oophoropexy. In girls who underwent oophoropexy, a lower rate of ovarian dysfunction was seen.

Key words: brain tumor/children/laparoscopy/oophoropexy/radiation


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Cancer of the nervous system is the most common solid tumor in children and often is treated with craniospinal radiation after surgical resection. Primary ovarian damage has been reported to occur in over 60% of girls receiving craniospinal radiation with or without chemotherapy for a brain tumor (Livesey and Brook, 1988Go). Laparoscopic oophoropexy in medulloblastoma patients before irradiation has been reported by us and others previously (Laufer et al., 1995Go; Lee et al., 1995Go). We aimed to determine whether laparoscopic unilateral oophoropexy prior to spinal radiotherapy effectively preserves ovarian function.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Institutional Review Board approval for a medical record/chart review and computer database research study was obtained from the Committee on Clinical Investigation at Children’s Hospital Boston and from the Office for the Protection of Research Subjects at the Dana-Farber Cancer Institute. A retrospective analysis of girls aged 18 and younger receiving spinal radiation for brain tumors between January 1990 and December 2001, some of whom underwent prophylactic oophoropexy, was performed. The latest record review included information available as of June 2003.

Oophoropexy was offered clinically to girls 18 years of age or younger who were about to undergo spinal radiation as part of a treatment plan for a brain tumor, beginning in 1990. The technical aspects of this procedure have been previously reported and are summarized below (Laufer et al., 1995Go). All oophoropexies were performed by a single surgeon (M.R.L.). The most mobile ovary was selected for transposition; if both were equally mobile the left ovary was usually selected. The ovary to be moved was mobilized by division of the ipsilateral utero-ovarian ligament and fallopian tube. [As the fallopian tube on the same side as the pexed ovary was sacrificed, assisted reproductive technologies (ART) may be required if the only remaining functional ovary is the transposed ovary.] The infundibulopelvic ligament was skeletonized to allow the ovary to be moved to the lowest point in the pelvis, and non-absorbable silk sutures were placed to attach the ovary to the uterosacral ligaments (Fig. 1). Finally, both the transposed and non-transposed ovaries were marked with titanium clips to aid in localization on radiation planning films.


Figure 1
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  		Figure 1: Laparoscopic view of right oophoropexy

Owing to its superior mobility in this case, the right ovary was selected for oophoropexy over the left ovary and was fixed to the uterosacral ligaments with silk suture to move it medially and deeper in the pelvis. UT, uterus; US, uterosacral ligament; ROV, right ovary; LOV, left ovary

 
All radiotherapy was initiated within 2 months after oophoropexy, and all transposed ovaries were noted to be in proper position on scout films. No delay in treatment attributable to recovery time from surgery occurred.

Ovarian function, the primary endpoint of the study, was determined by evidence in chart review of spontaneous breast development or the initiation or resumption of menstruation. Ovarian dysfunction was defined as an elevated (>20 mIU/ml) follicle-stimulating hormone (FSH) level at any time after cancer treatment or as prolonged amenorrhea (>6 months) persisting during our most current follow-up in girls who had regular menses before radiotherapy. The main independent variable of the study was treatment group (oophoropexy versus control).

Statistical analyses
The proportions of subjects experiencing ovarian dysfunction were compared between the oophoropexy and control groups using the Fisher’s exact test. In addition, exact binomial 95% confidence intervals were calculated. Subject characteristics and chemotherapeutic and radiation regimens were compared between the groups using the Wilcoxon rank sum test for continuous variables and Fisher’s exact test for dichotomous variables. All analyses were conducted using two-sided tests and a significance level of 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
There were 58 consecutive girls who received spinal irradiation for a brain tumor identified through the Harvard Joint Center for Radiation Therapy database. Chart review of all 58 patients was undertaken. Of these girls, 26 had undergone laparoscopic oophoropexy prior to radiation, and the remaining 32 patients served as the comparison group (Table I). No systematic information was available to determine who did or did not undergo oophoropexy, as this was largely physician-referral dependent. No surgical complications were reported in the 26 girls (aged 2–16 years) who underwent oophoropexy. Patients were excluded from further analysis of ovarian function if they were <12 years of age (expected to be prepubertal) at the time of the last documented visit, if documentation of their treatment or ovarian status was incomplete, if they had died before pubertal age or if they were lost to follow-up. We also excluded any patient who could not be evaluated for ovarian function due to panhypopituitarism. The clinical characteristics of all patients are summarized in Table I.


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  		Table I. Clinical characteristics of study population.

 
After applying the exclusion criteria listed above, 26 patients remained eligible for evaluation: 15 in the oophoropexy group and 11 patients in the comparison group. Of these 26 patients, 23 had a diagnosis of medulloblastoma. All patients underwent both spinal radiation therapy and chemotherapy. Overall, 13 of 15 patients in the oophoropexy group underwent puberty, and two (13%, 95% CI 0.2–40%) showed signs of ovarian failure. In comparison, 5 of 11 patients (45%, 95% CI 17–77%) in the non-oophoropexy group had evidence of ovarian dysfunction (P = 0.09) (Fig. 2).


Figure 2
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  		Figure 2: Incidence of ovarian dysfunction in patients treated with spinal radiation and chemotherapy for brain tumors, grouped by oophoropexy status

 
Clinical characteristics which may have altered the patient’s risk of ovarian failure were compared between the two groups (Table II). Median age at diagnosis, body surface area, length of follow-up and proportion of patients with high-risk tumors (defined as having metastatic disease, subtotal resection and/or age <2 at diagnosis) were not statistically different between the two groups. Chemotherapeutic and radiation regimens were also compared between the two groups (Table III). There was no significant difference between the median radiation dose to spine, duration of radiation or chemotherapy treatment and the doses of the four most commonly utilized chemotherapeutic agents: cisplatin, cyclophosphamide, vincristine and lomustine.


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  		Table II. Characteristics of patients that may impact risk of ovarian failure.

 

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  		Table III. Radiation and chemotherapeutic regimen of patients.

 
Table IV provides a detailed comparison of patients in each group who had either an elevated FSH level at any time after cancer treatment or prolonged amenorrhea (>6 months) persisting during our most current follow-up. Laboratory values were not available for some patients being followed in remote locations.


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  		Table IV. Characteristics of patients status post radiation therapy with an elevated FSH or persistent amenorrhea >6 months at time of latest follow-up

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have shown that oophoropexy may protect against radiation-induced ovarian failure in girls receiving spinal radiation. A high risk of ovarian dysfunction was seen in girls who received spinal radiation and chemotherapy without oophoropexy, similar to risks reported in the literature. In girls who underwent oophoropexy, the proportion with ovarian dysfunction was notably lower, although this difference was not statistically significant. This 10-year follow-up study is the largest reported to date evaluating the efficacy of laparoscopic oophoropexy in a pediatric population receiving spinal radiation for brain cancer.

It has long been recognized that therapeutic irradiation involving the pelvis is damaging to the ovaries. In one study of 16 girls who underwent bone marrow transplantation for acute leukemia using high-dose chemotherapy and total body irradiation, nine (56%) had spontaneous puberty and regular menstruation. Six of the nine had elevated gonadotrophin levels, however, raising questions as to the extent of their ovarian reserve (Sarafoglou et al., 1997Go). The remaining seven subjects required hormone replacement due to overt ovarian failure. Less frequently reported are the effects of craniospinal irradiation for intracranial tumors on ovarian function. Livesey and Brook (1988Go) reported primary ovarian damage in seven out of 11 (64%) girls treated with craniospinal irradiation alone and in nine out of 14 (64%) of those treated with both craniospinal irradiation and chemotherapy. The association with spinal irradiation was significant. In these two retrospective studies, no prophylactic measures were undertaken to spare fertility.

Yet in the past decade, the dramatically improved survival rates for childhood cancers have increased the demand for effective techniques to preserve fertility when gonadotoxic therapies are required. Options for prepubertal girls undergoing pelvic radiation are limited to ovarian tissue cryopreservation, which is still considered experimental (Donnez et al., 2004Go), and surgical oophoropexy. The prepubertal ovary normally is located higher in the pelvis compared with the relative final location in an adult and is more likely to be included in a craniospinal radiation field. Thus, surgical oophoropexy may serve to decrease exposure to radiation and improve future gonadal function.

Earlier studies of oophoropexy by laparotomy in girls receiving pelvic radiation for various cancers have shown improved gonadal function (Ray et al., 1970Go; Le Floch et al., 1976Go; Thomas et al., 1976Go; Gerbaulet et al., 1989Go; Damewood et al., 1990Go; Thibaud et al., 1992Go). A minimally invasive approach to the procedure is safe and effective in pediatric oncology patients and allows adjuvant therapy to begin earlier (Saenz et al., 1997Go). We have previously described the technique of laparoscopic oophoropexy with the hypothesis that unilateral oophoropexy by this less invasive method could also decrease ovarian failure after radiation therapy (Laufer et al., 1995Go). A unilateral oophoropexy was proposed since there is an ~40% chance of retaining normal function in the non-transposed ovary. If both ovaries are transposed and both fallopian tubes sacrificed, then the patient would be committed to ART to achieve conception. With the unilateral technique, ART may be required if only the pexed ovary remains functional. Choosing the left ovary may simplify the differential diagnosis of subsequent unilateral lower quadrant pain, decreasing confusion with appendicitis. With regard to transposition distance, even a separation of 1 cm between the ovary and the edge of the radiation field results in a large decrease in radiation dose: the radiation dose decreases from 40% at the field center to 8% in an ovary 1 cm away from the field edge, and drops to <5% in an ovary 2 cm from the field edge (Laufer et al., 1995Go).

There are few other reports in the literature evaluating the efficacy and safety of laparoscopic oophoropexy prior to radiation therapy in pediatric and adolescent patients. Most case reports and series describe the treatment and outcomes of adult women or of oophoropexy by laparotomy. Morice et al. (1998Go) studied bilateral laparoscopic ovarian transposition in 22 patients undergoing irradiation for pelvic tumors: three were under 20 years of age. None of the three girls underwent chemotherapy. One of the three patients experienced ovarian failure; the girl who experienced ovarian failure had been converted to laparotomy during laparoscopic oophoropexy and also received both brachytherapy and external beam radiation (the other two only received one or the other modality), which may have increased her risk of gonadotoxicity. Hart et al. (1999Go) reported an 18-year-old girl with medulloblastoma who underwent two laparoscopic surgeries to achieve oophoropexy to the pelvic brim and who had normal gonadotrophin levels 12 weeks after therapy. Tinga et al. (1999Go) described two girls aged 11 and 15 years with Hodgkin’s disease, one who underwent bilateral laparoscopic ovarian transposition to a fixed position behind the uterus (to lie beneath an external midline shield) and the other who had a laparoscopic oophoropexy to the level of the iliac crest. The younger patient had menarche at age 13, and the other girl resumed regular menstruation. Finally, Scott and Schlaff (2005Go) reported a 19-year-old girl with Hodgkin’s disease who underwent a laparoscopic bilateral medial oophoropexy prior to radiation therapy and resumed normal menstruation 16 months later. Twenty-two months after completion of therapy, she conceived spontaneously, although the pregnancy resulted in an early spontaneous abortion. Complications in all of these reports were rare. Although these small and heterogeneous studies suggest that laparoscopic oophoropexy is safe and effective, larger studies with longer follow-up and untreated comparison groups (if available) are needed to further evaluate the procedure.

Our study was restricted by small numbers of patients with a rare disease, a retrospective study design and the inherent limitations of a chart review. No statistically significant differences were identified between the two groups (Table I–III), likely due to limited power from the small number of cases of pediatric patients with brain tumors. In addition, differences in subject characteristics between the groups may have confounded results. Owing to the small number of cases of ovarian failure, however, we were not able to perform regression analyses to control for potential confounders. Moreover, longer follow-up time is needed to assess fully the effect of spinal radiation on fertility and any protection conferred by oophoropexy. Girls who were exposed to radiation may show signs of ovarian function at early follow-up, yet may possess decreased ovarian reserve that only manifests later in life as infertility and early menopause. Currently, there are no data on the ultrasound assessment of ovarian reserve (ovarian volume, antral follicle counts) in pediatric patients status post radiotherapy. Further investigation in this area is needed.

In counseling female survivors of childhood cancer, caregivers should also be aware of the effects of high-dose radiation on the prepubertal uterus and its future ability to carry a pregnancy. Abdominopelvic radiation in childhood may reduce adult uterine volume and blood flow (Critchley et al., 1992Go; Larsen et al., 2004Go) and increase the risk of spontaneous abortion, prematurity and low-birthweight infants (Sanders et al., 1996Go). Fortunately, the available data do not show an increased risk of congenital abnormalities (Nicholson and Byrne, 1993Go; Sanders et al., 1996Go). Still, if these women are able to achieve pregnancy, they must be considered high-risk obstetrical patients.

Our findings suggest that laparoscopic oophoropexy may protect against radiation-induced ovarian failure in girls. Further follow-up in a larger, adequately powered cohort is planned. It seems reasonable to offer laparoscopic unilateral oophoropexy prior to spinal irradiation for childhood brain tumors, since the probability of maintaining ovarian function is high, but further research is needed.


   Footnotes
 
* Presented in part at the 59th American Society for Reproductive Medicine Annual Meeting, San Antonio, TX, October 2003. Back


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Critchley HO, Wallace WH, Shalet SM, Mamtora H, Higginson J, Anderson DC. Abdominal irradiation in childhood: the potential for pregnancy. Br J Obstet Gynaecol (1992) 99:392–394.[Web of Science][Medline]

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Submitted on May 29, 2007; resubmitted on October 8, 2007; accepted on October 18, 2007.


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This Article
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