Abstract
Conservative and functional surgery is increasingly used in surgical oncology. Its aim is to preserve organs’ functionality and to reduce radical resection. Development of new surgical procedures in oncologic gynecologic surgery is a perfect example of this evolution. Although radical surgery remains the gold standard in the treatment of ovarian cancer, a conservative approach can be considered in patients with early-stages disease, in order to preserve their fertility function. These procedures were proposed to selected patients, depending on histologic subtypes and prognostic factors. Ovarian cancers are classified in epithelial (including borderline and malignant tumors) and non-epithelial cancer.
Introduction
Survival rates after cancer have increased significantly in recent decades; however, these treatments also have drawbacks, and patients must be informed of the long-term side effects of oncological treatments and the possible options for preserving the fertility of these patients. It is important to set out clearly the possible risks of developing ovarian failure or azoospermia with oncological treatments. These will depend on the age of the patients and on the type, dose and duration of chemotherapy, and on the field, dose and duration of radiotherapy.
The strategy must be individualized in each case depending on:
Patient’s age
Type and stage of the cancer; therapeutic plan to be followed
Biology of the tumor and potential for metastasis in ovary
Foreseeable long-term effects
Current or future desire to have children
Whether or not the patient has a partner/ spouse
Possibility or impossibility of delaying the start of ART treatment
If ovarian stimulation is possible, oocyte or embryo cryopreservation is the method with the greatest chance of success so far. Embryo vitrification it can only be applied if there is a male partner or if the couple accepts donor sperm. It is not indicated in single woman. Although embryo vitrification seems to be the more efficient strategy because the higher survival rates, ooocyte vitrification avoids ethical and legal concerns about the fate of surplus cryopreserved embryos if the patient finally do not use them. Moreover, in the recent years the optimization of oocyte vitrification protocols increase significantly the survival rate and clinical outcomes [1]. Is important provide patients with the center information about experience with oocyte vitrification and only cryopreservation programs with large experience and good results can offer oocyte cryopreservation as a safe strategy to preserve woman fertility [2]. Oocyte vitrification should actually be the method of choice. In both cases, it is very important before starting ovarian stimulation to clarify which are the safest protocols to be used in cancer patients, although current data suggest that in certain cases a cycle of ovarian stimulation with the appropriate drugs does not increase the risk of recurrence [3].
Ovarian Stimulation Protocols for IVF and Embryo Cryopreservation in Oncological Patients
First it has to be ruled out that ovarian stimulation is not harmful or contraindicated. It has to be taken in consideration that IVF cycle with oocyte retrieval may cause a delay in the initiation of oncological treatment that may not be acceptable in some oncological patients. If there is no serious impediment that contraindicates it, two special circumstances often arise: a short time to stimulate ovulation and the necessity of not reaching high estradiol levels and starting the ovarian stimulation before the chemotherapy. The results of the IVF cycle will be very poor if a course of chemotherapy has been performed [4].
In these cases, ovarian stimulation can be done using aromatase inhibitors in combination with gonadotropins. Tamoxifen was the first drug used in these protocols but letrozole soon proved to be just as safe and much more effective [5]. Letrozole is a powerful third-generation aromatase inhibitor; with a half-life of 48 h it significantly suppresses plasma estradiol levels. Data from recent publications suggest that letrozole is more effective than tamoxifen in ovulation stimulation protocols for oncological patients [6].
With regard to the gonadotropins, it seems to be better to use recombinant follicle stimulating hormone (FSH) preparations devoid of luteinizing hormone (LH) to limit the estradiol levels that will be reached during stimulation. To prevent early luteinization or premature ovulation it is fundamental to combine these drugs with a gonadotropin-releasing hormone (GnRH)-antagonist analogue so that we can act at any point in the menstrual cycle.
There is now evidence that the survival of oncological patients who have followed an ovarian stimulation protocol for an IVF cycle, and the freezing of any embryos that are obtained, is identical to that of patients who do not undergo this protocol [5].
If the oncologist authorizes a two-week delay in the treatment, ovarian stimulation can be carried out for embryo cryopreservation purposes, regardless of the cycle day. If stimulation starts in the late follicular phase, the already selected leading follicle will not be taken into account and the GnRH antagonist will be administered whenever the next leading follicle of the cohort we are recruiting measures 14 mm. If stimulation starts in the luteal phase, the endogenous progesterone blocks the endogenous LH peak, so there is no need to administer GnRH antagonist. In cases of hormone-sensitive tumors, aromatase inhibitors co-treatment is recommended (5 mg/day from the beginning of the stimulation until three to four days after oocyte retrieval). Ovulation trigger will be carried out with GnRH agonists in order to avoid ovarian hyperstimulation syndrome.
Outcome of Embryo-Freezing Programs
Since the first pregnancy obtained from cryopreserved human embryos [6], the yield and safety of embryo cryopreservation programs have improved notably with successful freezing of zygotes and cleaving of embryos and blastocysts, and pregnancies are regularly obtained after thawing and transfer of embryos in any of these stages. Our first pregnancy after transferring a previously frozen embryo was obtained even though only one of the embryo’s original four cells survived thawing and was transferred [7].
It is accepted that 15–20% of the 3 million children born after in vitro fertilization (IVF) were conceived following the transfer of embryos that had previously been frozen and thawed. It means that these 500,000 or so children make up a wide population that proves the efficacy and the safety of embryo cryopreservation [8, 9].
In our experience, with our FET program including two different periods (1987-2011 using slow freezing protocol and 2012–2019 with vitrification), and with 53,474 embryos thawed, we had a global survival rate of 73%. A total of 20,205 cryoreplacements were performed leading to the birth of 4,910 children and with a birth-per-cryoreplacement rate of 23% (Table 19.1).
Table 19.1 Institut Universitari Dexeus embryo freezing program: 1987–2019
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