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Emergency Fertility Preservation for Female Patients with Cancer: Clinical Perspectives

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Emergency Fertility Preservation for Female Patients with Cancer: Clinical Perspectives ANTICANCER RESEARCH 35: 3117-3128 (2015) Review Emergency Fertility Preservation for Female Patients with Cancer: Clinical Perspectives MAHMOUD SALAMA and PETER MALLMANN Department of Gynecology and Obstetrics, Medical Faculty, University of Cologne, Cologne, Germany Abstract. To explore the new as well as the currently Almost one in 51 women will suffer from an invasive available options and strategies that can be used for cancer by the age of 39 years and hence will receive cancer emergency fertility preservation of female cancer patients, a treatment. The most common forms of invasive cancer in systematic literature review was performed for all full-text women are breast (29%), lung (13%), colorectal (8%), articles published in PubMed in English language in the past uterine and cervical (6%) cancer, thyroid carcinoma (6%), 15 years according to the Preferred Reporting Items for lymphoma (4%), melanoma (4%), leukemia (3%), kidney Systematic Reviews and Meta-Analyses (PRISMA) (3%) and pancreatic (3%) cancer (2). Cancer treatments such guidelines. Although under-utilized, several established, as chemotherapy and radiotherapy act through inhibition of experimental and debatable options exist and can be used DNA function and cell division, resulting in cytotoxicity and for emergency fertility preservation in females. Such options cell damage (6). After chemotherapy and radiotherapy, the include emergency ovarian stimulation, embryo freezing, egg probability of conception in female cancer survivors is freezing, ovarian tissue freezing and autotransplantation, in markedly diminished by 30-50%, with an increased risk of vitro maturation, and ovarian protection techniques. This delivering pre-term and of babies with low birth weight (7- article describes and evaluates in detail the advantages and 13). However, when reproductive organs are exposed to disadvantages of each option and suggests a new aggressive chemotherapy and radiotherapy, irreversible comprehensive multi-step strategy for emergency fertility damage occurs leading to permanent loss of fertility (14-17). preservation of female patients with cancer. Alkylating chemotherapy such as cyclophosphamide, ifosfamide and busulphan, in addition to ionizing radiotherapy Each year, millions of women worldwide are diagnosed to the abdomen and pelvis, or total-body irradiation are the with cancer. In the year 2012, the number of new cancer most aggressive cancer treatments to the ovaries and uterus cases in women was approximately 1.2 million in the (18, 19). The degree of ovarian and uterine damage is related European Union, 0.7 million in the United States and 6.6 to the dose, site, and fractionation of the chemotherapy and million worldwide (1). About 10% of those women were in radiotherapy, as well as the age of the patient at the beginning their reproductive years. Due to recent advances in of treatment. Severe ovarian damage can lead to premature treatment, almost 90% of young women with cancer can ovarian failure due to complete depletion of follicles and survive when they are diagnosed-early (2). However, they oocytes. Comparably, severe uterine damage can lead to may suffer from fertility loss due to irreversible recurrent miscarriage, pregnancy loss, preterm labor, and low reproductive damage caused by aggressive chemotherapy birth weight due to disruption of uterine vasculature (20-23). and radiotherapy (3-5). As the survival rate of young women with cancer is increasing, the need to develop effective and individualized fertility-preservation strategies is also increasing (24, 25). Unfortunately, the probability of female fertility loss increases Correspondence to: Professor Dr. med. Peter Mallmann, Head of tremendously when aggressive cancer treatment is immediately Gynecology and Obstetrics Department, Medical Faculty, University administered as in treatment of highly invasive malignancies. of Cologne, Kerpener St. 34, 50931 Cologne, Cologne, Germany. In such cases, developing an emergency fertility-preservation Tel: +49 02214783440/+49 02214784900, Fax: +49 02214784929, strategy becomes absolutely necessary (26, 27). The aim of the e-mail: [email protected] present article was to explore the new and the currently Key Words: Emergency fertility preservation, cancer, cryopreservation, available options and strategies that can be used for emergency autotransplantation, in vitro maturation, oncofertility, review. fertility preservation of female patients with cancer. 0250-7005/2015 $2.00+.40 3117 ANTICANCER RESEARCH 35: 3117-3128 (2015) Materials and Methods disadvantages of each option from a clinical perspective. We also suggest a new comprehensive multi-step strategy According to the Preferred Reporting Items for Systematic Reviews for emergency fertility preservation of female patients with and Meta-Analyses (PRISMA) guidelines (28), a systematic review cancer that can be carried out by oncologists, gynecologists of the literature in the past 15 years was performed for all full-text and reproductive biologists. articles published in PubMed in English between 1 January 2000 and 31 December 2014 to explore the new and currently available Emergency Ovarian Stimulation options and strategies that can be used for emergency fertility preservation of female patients with cancer. Based on these inclusion criteria, the following electronic search strategy was In cases of emergency fertility preservation, conventional performed in PubMed: (emergency female fertility preservation) OR ovarian stimulation is not preferred as it may take up to female fertility preservation) OR oncofertility) AND female cancer several weeks. Conventional ovarian stimulation may also patients) AND cryopreservation) AND full text[sb] AND result in ovarian hyperstimulation syndrome that would ("2000/01/01"[PDat] : "2014/12/31"[PDat] ) AND Humans[MeSH] require further treatment leading to a delay of primary cancer AND English[lang] AND Female[MeSH Terms])). The full-text articles identified from the initial search underwent therapy. In addition, conventional ovarian stimulation is screening for titles and abstracts, then were checked for eligibility contraindicated in patients with estrogen-sensitive tumors, according to the inclusion criteria. Only the full-text articles such as breast and endometrial cancer, as it is associated with focusing primarily on the new and currently available options and high levels of serum estradiol (46-53). strategies that can be used for emergency fertility preservation of Recently, some alternative ovarian stimulation protocols female patients with cancer were included and fully reviewed. Data within a two-week time frame have been attempted and were extracted from the text, tables, graphs and references of the shown promising results for emergency fertility preservation included articles. in patients with breast cancer and hematologic malignancies. Results Examples of these alternative protocols are luteal-phase or random-start protocol (54-57) and follicular-phase protocols A total of 308 full-text articles were identified from the using letrozole (aromatase inhibitor) (58-63) or tamoxifen initial search. Almost 60% of these articles were published (selective estrogen receptor modulator) (64, 65). Although in the past five years. After screening titles and abstracts, all promising, women with cancer showed lower response to 308 full-text articles were checked for eligibility according ovarian stimulation in comparison to healthy age-matched to the inclusion criteria. Only 251 full-text articles focusing women according to a recent meta-analysis (66). primarily on the new and currently available options and Consequently, extrapolation of conventional in vitro strategies that can be used for emergency fertility fertilization, embryo freezing, and egg freezing results to preservation of female patients with cancer were included female patients with cancer should be done with caution (67, and fully reviewed. The PRISMA flow diagram of the 68). After successful emergency ovarian stimulation, mature systematic review process is illustrated in Figure 1. oocytes can be retrieved for further embryo freezing or egg Regarding fertility preservation of female patients with freezing options. cancer, many guidelines and recommendations have been published by the American Society of Clinical Oncology Embryo Freezing (ASCO) (29, 30), European Society for Medical Oncology (ESMO) (31, 32), American Society for Reproductive Embryo freezing is the first established cryopreservation Medicine (ASRM) (33-35), International Society for method for female fertility preservation and is still Fertility Preservation (ISFP) (36-39), Fertility Preservation considered the gold-standard option. It involves Network (FertiPROTEKT) (40), and US Oncofertility cryopreservation of in vitro-fertilized mature oocytes via Consortium (41, 42). Some of these guidelines were not slow freezing or vitrification (29-42). Nevertheless, identified in the initial search. However, the final reference vitrification is now more preferred due to a better post-thaw list was generated on the basis of originality and relevance survival rate (69-71). As an emergency fertility-preservation to the broad scope of this review. procedure, embryo freezing requires emergency ovarian Although under-utilized, several established, stimulation as described above, mature oocyte retrieval, and experimental and debatable options exist and can be used fertilizing sperm for in vitro fertilization. Therefore, it is for emergency
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