1 Department of Obstetrics, Gynaecology and Reproductive Medicine, Polyclinique de l'Hôtel-Dieu, 13 Boulevard Charles de Gaulle, 63033 Clermont-Ferrand Cédex 1, France
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Abstract |
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Key words: borderline ovarian tumour/IVF/radical surgery
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Introduction |
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Case report |
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Post-operatively, the patient was informed of her oncological status and that extensive surgical treatment was required, including at least a bilateral oophorectomy. The different options to `preserve' her reproductive potential were discussed. Two options were presented to the patient. The first one was immediate surgical treatment with uterine conservation and subsequent oocyte donation. The second was to perform an `urgent' IVF in order to freeze embryos and to perform the surgical treatment after oocyte retrieval. The patient was advised that this second solution presented more oncological risks in theory than the first, but it was the only chance to obtain a baby with her own genetic material (Ovarian Cancer, 1994). She and her male partner finally opted for the second alternative after 2 days of reflection.
The patient was immediately treated with long-acting gonadotrophin-releasing hormone (GnRH) analogues (Decapeptyl retard 3 mg; Laboratoires Ipsen-Biotech, Paris, France) and then stimulated with human menopausal gonadotrophin (HMG; Neopergonal, Serono Laboratories, Boulogne, France). Fifteen days later, pituitary down-regulation was obtained, and a step-down ovarian stimulation protocol was started. After 10 days of HMG stimulation, 16 oocytes were harvested; 10 embryos were obtained and frozen (two at 2-cell stage, two at 3-cell stage, five at 4-cell stage and one at 5-cell stage). The cryopreserved embryos were frozen using propanediol as cryoprotectant. Two days later, radical surgery was performed that included bilateral oophorectomy, omentectomy, iliac and lomboaortic dissection. At the time of radical surgery, ovarian tissue was also frozen according to the Hogden recommendations (Toth et al., 1994). All the procedures were managed by laparoscopy. The pathologist found no lymph node metastasis and no lesions on ovaries. CA 125 was slightly elevated (49 IU/ml).
Regular marker evaluation and ultrasound check-up did not show any recurrence. One year later the patient asked for the transfer of the frozen embryos. As initially explained to the patient, a laparoscopic second-look was performed in order that embryos were not transferred without being as sure as possible that there was no recurrence. Thirteen months after radical surgery, a fifth laparoscopy confirmed the absence of any residual tumour. Peritoneal biopsies and cytology were negative. Two months later, two thawed embryos were replaced. The substitution treatment included 2 mg micronized oestradiol per day (Progynova 1 mg, Schering Laboratories, Lys-lez-Lannoy, France) from day 1 to day 28, and vaginal progesterone (Utrogestan, Laboratories Besins Iscovesco, Paris, France) at a dose of 200 mg per day from days 14 to 28. The embryos were transferred on day 17. One embryo implanted. The substitutive treatment was continued during 2 months. It included 4 mg of micronized oestradiol and 300 mg of oral progesterone. The patient had a normal monofetal pregnancy and delivered vaginally a healthy boy, 3830 g, 50 cm, Apgar 10/10/10, 36 weeks after transfer. Up to now (June 2000), this patient has had no clinical, biological or radiological sign indicative of a recurrence of her cancer.
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Discussion |
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All the surgical procedures were performed by laparoscopy, which could be questioned because of the higher risk of crushing the lesions with peritoneal and parietal dissemination (Michel et al., 1995). Everything was carried out according to oncological rules. Tissue samples were extracted from the abdomen in endobags. The surgeons were highly experienced in oncological laparoscopic surgery. The advantage of laparoscopy in these circumstances is the possibility to repeat the procedures without major discomfort for the patient. It is very probable that without the ability to treat by laparoscopy this case would have been concluded earlier with radical treatment. Laparoscopy permits a therapeutic strategy to be defined with more accurate staging and without significant loss of time and opportunity (Pouly et al., 1997
). Before each laparoscopy, the patient was advised that a second operation might be necessary a few days later according to the operative and histological findings. Using only laparotomy, such an accurate prediction is impossible. The risk of carcinomatous spread to the abdominal wall might be a point against the laparoscopic strategy. This risk seems to be increased in animal models, but the situation in this case was different in two ways: it was an LMPT about which no clinical data have ever been reported of an increased risk, and all precautions were taken to minimize this risk (low abdominal pressure, and extraction in endobags).
Several case reports are available about successful pregnancy after conservative surgery for early-stage cancer (Niwa et al., 1995; Perrin et al., 1999
). At present, there is no evidence of any adverse effect of pregnancy on the course of advanced stage borderline tumour of the ovary (Hoffman et al., 1999
). Indeed, neither pregnancy status at time of diagnosis nor occurrence of subsequent term pregnancy have been found to alter the prognosis (Trimble and Trimble, 1994
). A pregnancy obtained by IVF 2 years after conservative surgery has been reported for serous LMPT (Hoffman et al., 1999
). In addition, 11 patients receiving ovulation induction have been shown to have no apparent effect on their prognosis (Gottleib et al., 1998
). In fact, the use of both IVF and donor oocytes has been reported in patients treated for borderline tumour (Mantzavinos et al., 1994
; Lawal and Lynch, 1996
). In our case, the impossibility of natural fertility preservation led us to propose an IVF with embryo cryopreservation before radical surgery. This strategy enabled oocyte donation to be avoided but imposed a 1 month delay and ovum retrieval, while two laparoscopies revealed recurrent lesions of LMPT. The absence of invasion and the almost complete treatment for macroscopic lesions during the third laparoscopy support the view that this delay was acceptable without dramatically decreasing the vital prognosis of this patient. A single cycle of ovulation induction preparing for IVF can be equivalent to 2 years of normal menstrual cycles in terms of the number of follicles produced and oestrogen concentration achieved (Fishel and Jackson, 1986). Animal models of ovarian tumours suggest that gonadotrophins play a central role in the development or proliferation of these tumours (Bandera et al., 1995
). It has been proposed that the pattern of excessive hormonal stimulation is also applicable to human epithelial ovarian cancer (Cramer and Welch, 1983
). Furthermore, FSH binding sites have been identified in epithelial ovarian cancer cell lines and FSH has been shown to stimulate papillary serous ovarian cancer cell division (Wimalasena et al., 1992
). In 1996, of the 15 published reports of ovarian carcinoma associated with fertility drug use, nine were of borderline histology (Bristow and Karlan, 1996
). The ovarian cancer risk was 2.8-fold higher for the patients treated for infertility (Whittemore et al., 1992
). In fact, the risk is not higher if the patient becomes pregnant after the stimulation. Inversely, unsuccessful embryo transfer after stimulation leads to a higher risk. Currently available data in the literature suggest that an association between ovulation induction and ovarian cancer does not necessarily indicate a causal effect (Tarlatzis et al., 1995
). For all these reasons, we thought that to delay the radical surgery did not represent a significant reduction in the chance to survive, and also that the high concentration of oestrogen induced by stimulation would not incur a major increase in risk of spread of the tumour. No data except ours are available concerning this opinion (Pouly et al., 1997
). Nevertheless, the patient was advised of the uncertainty concerning this point and accepted it.
The duration of the interval prior to uterine transfer of thawed embryos is debatable. In case of invasive cancer, we thought that the delay should be 2 years because most recurrences occur during this period even if some have been reported to occur as much as 6 years later (Lansac, 1971). In the case of LMPT, the situation is different. The delay for recurrence is generally much longer and it can occur up to 20 years later (Leake et al., 1992
). We felt that before trying to obtain a pregnancy, it was ethically necessary to ascertain a non-recurrence status. Laparoscopy with peritoneal cytology and biopsy was therefore mandatory because metastasis of <1 cm can be missed by radiological imaging or marker evaluation. Therefore, a fifth laparoscopy, including peritoneal cytology and biopsies, was performed. The absence of recurrence authorized the transfer of two thawed embryos leading to a monofetal normal pregnancy. This couple still have eight frozen embryos, and 3.5 years after the initial diagnosis, this patient is free of recurrence.
In conclusion, even if a stage IIIA serous borderline tumour needs a bilateral oophorectomy, it is possible to perform conservative maximal debulking, ovum retrieval for IVF and embryo cryopreservation before radical surgery. Secondly, an embryo transfer can successfully avoid oocyte donation. This observation underlines the great advantage of close collaboration between oncological and reproductive units in the treatment of cancers. In our opinion, this strategy should preferably be reserved for women <30 years old but may be extended to those aged 35 years.
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Notes |
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References |
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Submitted on February 16, 2000; accepted on July 11, 2000.