Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo
Dr. Rebar reports he is the chair of the data and safety monitoring board for Myovant Sciences.
SYNOPSIS: A large retrospective cohort analysis from a single medical center suggests that fertility preservation in women with borderline ovarian tumors does not decrease length of survival.
SOURCE: Helpman L, Yaniv A, Beiner ME, et al. Fertility preservation in women with borderline ovarian tumors — how does it impact disease outcome? A cohort study. Acta Obstet Gynecol Scand 2017:96:1300-1306.
Borderline ovarian tumors (BOT), sometimes termed ovarian tumors of low malignant potential, account for the minority of all epithelial ovarian tumors but are diagnosed much more commonly in women of reproductive age than invasive cancers. This prompted investigators at one medical center to assess the effect of fertility-preserving surgery on disease outcomes, including recurrence and survival.
A historical cohort of 213 sequential women with BOT were identified with sufficient data for analysis from a prospectively maintained database between the years 1981 and 2011. Mean follow-up for the cohort was 75 months, with a total follow-up period of 1,331 person-years. The mean age in the cohort was 38.7 years, with 132 (62%) being ≤ 40 years of age. A total of 112 (85%) of the younger women (age ≤ 40 years) and 124 women in all had fertility-preserving surgery, with such surgery defined as surgery sparing the uterus and some ovarian tissue to allow spontaneous conception in the future. There were 67 pregnancies in 42 of the 112 women (38%) younger than 40 years of age who had fertility-preserving surgery, with more than one pregnancy documented in 22 women. In all, 50 patients (24%) developed recurrences, with 40 of those having had fertility-sparing surgery. Recurrence was localized in 37 patients and disseminated (usually peritoneal) in 11 cases. Twenty patients (9%) died over the course of follow-up, with 11 succumbing to their disease but nine dying from other causes (and no evidence of recurrence). Six of those 11 cases (55%) had fertility-preserving surgery. Of note is the fact that eight of those dying of their disease had evidence of capsule rupture, tumor on the ovarian surface, or malignant cells in the ascites fluid or peritoneal washings (stage 1C) at the time of staging surgery. On multivariate analysis, fertility preservation (hazard ratio [HR], 2.57; 95% confidence interval [CI], 1.1-6; P = 0.029) and advanced stage of 1C or greater (HR, 4.15; 95% CI, 2.3-7.6; P < 0.001) were associated independently with recurrence on multivariate analysis. Fertility preservation was associated with shorter disease-free survival (mean of 177 months for women having fertility-sparing surgery and of 235 months for those who did; P < 0.001). However, both fertility preservation and ovarian conservation were not associated with overall survival by either log-rank test or the Kaplan-Meier method for stage 1 disease.
The findings of this study become more relevant as women delay childbearing until later in life. Although retrospective and from a single institution, the results are reassuring. It is unlikely that a large, sufficiently powered, randomized trial of fertility-sparing surgery for early-stage BOT ever will be conducted. Although the risk of mortality with fertility-sparing appears low, it also appears that the risk of recurrence is increased. Thus, patients with BOT contemplating fertility preservation must be counseled carefully to pursue childbearing as soon as possible. There are no guarantees that the disease will not recur and lead to death.
It is important to note that many findings in this study are consistent with prior reports. The low mortality of < 5% is comparable to another European study.1 The fact that fertility-sparing surgery had little effect on survival is consistent with prior studies2-5 and is generally attributed to the potential for further surgery to cure any recurrences. A relatively recent systematic review of fertility preservation in BOT concluded that the risk of recurrence for conservatively managed early disease is 13%, with the risk rising to 38% in advanced disease.5 In this study, consistent with the previously mentioned studies, univariate analysis found an association between recurrence and a number of other factors, including disease stage and peritoneal spread, CA 125 levels, and serous histology. A pooled estimate for spontaneous pregnancy after conservative surgery for BOT was 54% (95% CI, 38-70%),5 with more pregnancies occurring in women with non-serous (mainly mucinous) neoplasms.6 Few women in this study received adjuvant chemotherapy, but those who did had an increased risk of dying, consistent with a Cochrane review7 not supporting its use. These data are consistent with a recent review noting the risk of progression to invasive BOT was only 2-3%.8
There is one small randomized trial published in 2007 and updated in 2010 that assists us in counseling women who desire a future pregnancy.9,10 Thirty-two patients with bilateral BOT were treated laparoscopically and randomized to bilateral cystectomy vs. unilateral salpingo-oophorectomy on the side with the larger lesion and contralateral cystectomy. Follow-up at 81 months revealed no differences in the cumulative rates of recurrence. However, the cumulative pregnancy rate and the cumulative rate of a first pregnancy were higher with bilateral cystectomy.9 Those women with bilateral cystectomy had a shorter time to first recurrence and a higher rate of radical treatment of the recurrence.10 These data can be interpreted as suggesting that bilateral cystectomy should be performed for bilateral disease if technically feasible for fertility preservation. Extrapolating this further suggests that unilateral cystectomy should be preferred over unilateral salpingo-oophorectomy for unilateral disease in women desiring future children. Although biopsy of a contralateral normal-appearing ovary is suggested by some, the yield is low and the risk of causing adhesions decreasing fertility is real.5
This study does not tell us about the effect of assisted reproduction in women with BOT. This too has significance, as more women delay childbearing and seek assistance for relative infertility. Preservation of the uterus if both ovaries are removed allows for future assisted reproduction.11,12 In vitro fertilization has been reported only in case reports and small series.5 As a consequence, little is known about the effects of fertility drugs after conservative treatment of BOT but it has been used after appropriate counseling. Because freezing ovarian tissue that appears grossly normal may contain and subsequently introduce malignant cells with re-transplantation, this approach to infertility would appear to be contraindicated at least at present.
- du Bois A, Ewald-Riegler N, de Gregario N, et al. Borderline tumours of ovary: A cohort study of the Arbeitsgemeinshaft Gynakologische Onkologie (AGO) Study Group. Eur J Cancer 2013;49:1905-1914.
- Morice P, Camatte S, El Hassan J, et al. Clinical outcomes and fertility after conservative treatment of ovarian borderline tumors. Fertil Steril 2001;75:92-96.
- Fauvet R, Poncelet C, Boccara J, et al. Fertility after conservative treatment for borderline ovarian tumors: A French multicenter study. Fertil Steril 2005;83:284-290.
- Tinelli R, Malzoni M, Cosentino F, et al. Feasibility, safety, and efficacy of conservative laparoscopic treatment of borderline ovarian tumors. Fertil Steril 2009;92:736-741.
- Darai E, Fauvet R, Uzan C, et al. Fertility and borderline ovarian tumor: A systematic review of conservative management, risk of recurrence and alternative options. Human Reprod Update 2013;19:151-166.
- Kanat-Pektas M, Ozat M, Gungor T, et al. Fertility outcome after fertility surgery for borderline ovarian tumors: A single center experience. Arch Gynecol Obstet 2011;284:1253-1258.
- Faluyi O, Mackean M, Gourley C, et al. Interventions for the treatment of borderline ovarian tumours. Cochrane Database Syst Rev 2010;(9):CDC007696.
- Morice P, Uzan C, Fauvet R, et al. Borderline ovarian tumour: Pathological diagnostic dilemma and risk factor for invasive or lethal recurrence. Lancet Oncol 2012;13:e103-e115.
- Palomba S, Zupi E, Russo T, et al. Comparison of two fertility-sparing approaches for bilateral borderline ovarian tumours: A randomized controlled study. Hum Reprod 2007;22:578-585.
- Palomba S, Falbo A, Del Negro S, et al. Ultra-conservative fertility-sparing strategy for bilateral borderline ovarian tumours: An 11-year follow-up. Hum Reprod 2010;25:1966-1972.
- Laval AH, B-Lynch C. Borderline ovarian cancer, bilateral surgical castration, chemotherapy, and a normal delivery after ovum donation and in vitro fertilization-embryo transfer. Br J Obstet Gynaecol 1996;103:931-932.
- Gallot D, Poully JL, Janny L, et al. Successful transfer of frozen-thawed embryos obtained immediately before radical surgery for stage IIIa serous borderline ovarian tumour: Case report. Hum Reprod 2000;15:2347-2350.