Ovarian tissue cryopreservation: Low usage rates and high live-birth rate after transplantation.

INTRODUCTION: The likelihood of survival after cancer treatment among young women with cancer has increased considerably, quality of life after treatment has drawn more attention. However, in young fertile women, fertility preservation is an important issue with regard to quality of life. One of the options of fertility preservation is ovarian tissue cryopreservation. The purpose of this follow-up study is to present our clinical experiences and evaluate the long-term follow up of ovarian cryopreservation to improve future patient selection. MATERIAL AND METHODS: From July 2002 to December 2015 at the Leiden University Hospital, the Netherlands, 69 young women underwent ovarian tissue cryopreservation when they were at risk of iatrogenic premature ovarian insufficiency. Follow-up data with regard to ovarian function were obtained until October 2018, from medical records and questionnaires. RESULTS: Of the 69 women in whom ovarian tissue cryopreservation was performed, 12 died (15.9%), 57 were approached to participate, of which 6 were lost to follow up. The indications for ovarian tissue cryopreservation were malignant (81.1%) and benign (18.9%) diseases in which gonadotoxic treatment was scheduled. In total, twenty women (39.2%) are known to have premature ovarian insufficiency due to gonadotoxic treatment. Fifteen women conceived spontaneously, and delivered 25 babies. In this cohort, the usage rate of autotransplantation is 8.7% (7/69). In total, nine autotransplantations of cryopreserved ovarian tissue were performed in seven patients (of which 1 ovarian tissue cryopreservation was performed in another hospital) after which 6 babies were born to four women, giving a live-birth rate of 57%. CONCLUSIONS: Ovarian tissue cryopreservation followed by autotransplantation is an effective method to restore fertility (live-birth rate of 57%). The usage rate of 8.7% (6/69) indicates that more knowledge about the risk of premature ovarian insufficiency after gonadotoxic treatment is needed to be able to offer ovarian tissue cryopreservation more selectively.

Ovarian function after ovarian transposition and additional pelvic radiotherapy: A systematic review.

OBJECTIVE: To investigate the ovarian survival (OS) after ovarian transposition (OT) and pelvic radiation. DESIGN: Systematic review. Electronic databases were searched to identify studies on OT prior to external beam radiation therapy (EBRT, to the pelvic). Primary outcome was the ovarian function after radiotherapy and ovarian transposition. Secondary outcomes were complication-rate. Only studies in English, German or French were included. SETTING: Not applicable. PATIENTS: Fertile women undergoing ovarian transposition prior to pelvic radiation therapy. INTERVENTIONS: We included all studies, containing >5 patients, treated with OT prior to radiation therapy. MAIN OUTCOME MEASURE: Ovarian function. RESULTS: Our search yielded a total of 1130 studies of which 38 were eligible with a total of 765 patients. All studies were cohort studies or case-series. Heterogeneity among studies could not be rejected hence meta-analysis could not be performed. OS after OT and EBRT ranged from 20% to 100%. The median follow-up ranged from 7 to 102 months. OS was higher after OT and brachytherapy (OS 63.6-100%) when compared to OT and EBRT (20-100%) and OT concomitant chemoradiotherapy (0-69.2%). Only 22 studies (with 112 patients) reported on complications: among these studies the complication-rate was 0%-28.6%. CONCLUSION: From our systematic review of literature we conclude that the preservation of ovarian function after OT prior to EBRT is successful in 20-100% of patients. Most favorable outcome with regard to preservation of ovarian function is seen in patients after OT and BT, followed by OT and EBRT and OT and RT combined with chemotherapy.

Effects of controlled ovarian stimulation on toxicity of TAC chemotherapy in early breast cancer patients.

BACKGROUND: Oocyte and embryo cryopreservation, using controlled ovarian stimulation (COS), are common fertility preservation methodologies in breast cancer patients receiving gonadotoxic neo (adjuvant) chemotherapy (CT). The effects of COS and peak estradiol levels on CT-induced side effects are unknown. PATIENTS AND METHODS: Eighteen patients with stage II and III breast cancer underwent oocyte or embryo cryopreservation at Leiden University Medical Center before receiving docetaxel, adriamycin, and cyclophosphamide (TAC) CT (COS group). A control group (N=18) was retrospectively selected from breast cancer patients, aged between 18 and 40, who underwent TAC CT without fertility preservation. CT -induced toxicity in the 2 groups was compared using χ2 analysis. Associations between peak estradiol levels and distinct stimulation protocols and side effects in the COS group were investigated by using regression analysis. RESULTS: Patient characteristics between both groups were similar, except for a lower age in the COS group vs the control group (30.5 vs 35.2 years, P=0.005). No differences were seen in grade III/IV side effects between both groups. In the COS group, an increase in thrombopenia grade I/II was seen, while grade I/II stomatitis and constipation were significantly lower in the COS group as compared with the control group (P=0.006 and P=0.008, respectively). In the COS group, no association was found between the peak estradiol levels and distinct stimulation protocols and side effects of CT. CONCLUSION: COS prior to TAC CT was not associated with an increase in grade III/IV side effects. Interestingly, COS may have a protective effect on mucositis and constipation. Moreover, the peak estradiol levels and distinct stimulation protocols had no effect on grade III/IV side effects in our study.

Feasibility and effects of a decision aid about fertility preservation.

This paper reports on the feasibility and preliminary effects of a decision aid (DA) about female fertility preservation (FP). We conducted a pilot multicentre randomized controlled trial of women with breast cancer aged 18-40 who were randomized to brochures or the DA. Over 18 months, 62 women were eligible, of which 42 were invited by their healthcare provider (74%) to participate in the study. A total of 36 women signed up for participation and 26 (72%) were randomized to brochures (n = 13) or the DA (n = 13). In both groups, many women (87%) read the brochures and eight women used all available brochures. In the intervention group, 7/13 women logged in to the DA. Women who received brochures had slightly less decisional conflict, whereas knowledge improved in both groups. Our results indicate that both brochures about FP and a detailed DA have beneficial effects with regard to knowledge, but the DA seemed to introduce slightly more decisional conflict (DC) than the brochures. Although we encountered challenges with recruitment, our design and measurements seem feasible and the effects of the information materials seem promising, hence justifying conducting a larger study.

Validation of a Dutch Version of the Reproductive Concerns Scale (RCS) in Three Populations of Women.

We investigated the psychometric properties of a Dutch version of the Reproductive Concerns Scale (RCS). Questionnaires (N = 515) were administered to 90 women with breast cancer, 227 women with fertility problems, and 198 healthy controls. Principal axis factor analysis suggested a one-factor structure with 11 items (breast cancer patients R(2) =.48, α =.87, ICC =.95; women with fertility problems R(2) =.45, α =.89, ICC =.86). Women with fertility problems reported the most concerns (M = 21.8, SD = 9.6), followed by breast cancer patients (M = 14.8, SD = 10.0) and healthy controls (M = 6.4, SD = 7.0). Theoretically related constructs were correlated to the RCS (.33 < r >.73). The RCS seems to be a valid tool for assessing women's reproductive concerns.

Women's experiences with information provision and deciding about fertility preservation in the Netherlands: 'satisfaction in general, but unmet needs'.

OBJECTIVE: It is not well-known how women receiving counselling consultation about fertility preservation (FP) in the Netherlands perceive the information provision about and referral for FP in the oncology setting. The aim of this study was to qualitatively explore women's experiences with the (process of) information provision about the gonadotoxic effects of cancer treatment and about FP and the decision-making process and to obtain their recommendation for improvements. METHODS: Semi-structured interviews with female patients with cancer who had received a counselling consultation on FP (at 18-40 years of age). RESULTS: Thirty-four interviews were held (response rate 64%). Information provision was considered to be important. Overall, women were satisfied with the timing and the content of the information, but women were less positive about the need to be assertive to get information, and the multiplicity of decisions and actions to be carried out in a very short time frame. CONCLUSIONS: Information provision on gonadotoxic effects of cancer treatment and about FP was overall deemed sufficient, timely and important. Women recommended standardization of the information provision, improvement of communication among clinicians and medical centres, and availability of FP-specific patient information materials to improve future information provision processes.

Development of a Decision Aid about fertility preservation for women with breast cancer in The Netherlands.

OBJECTIVES: To improve information provision about fertility preservation for breast cancer patients in the Netherlands, a web-based Decision Aid (DA) with additional values clarification exercise was developed according to the International Patient Decision Aid Standards criteria. This study reports on development of the DA. METHODS: Development consisted of four stages: (I) development of a draft DA, (II) acceptability of the draft DA to patients, (III) understanding (knowledge) in healthy populations, (IV) acceptability of the revised DA among patients and physicians. The study population consisted of 185 participants: 20 patients, 17 physicians and 148 healthy volunteers. RESULTS: The draft DA was considered to be relevant and understandable by patients, physicians and healthy volunteers. The values clarification exercise needed adaptation in explanation and navigation, which was done after stage II. Knowledge scores improved by 18% for lower educated women (from 4.1 (41%) to 5.9 (59%) correct answers), and by 34% for higher educated women after viewing the website (from 3.9 (39%) to 7.3 (73%) correct answers). Design of the DA was evaluated to be clear, but not always very appealing. CONCLUSIONS: The DA was regarded as a relevant source of information that seemed coherent and understandable.

Oncologists' practice and attitudes regarding fertility preservation in female cancer patients: a pilot study in the Netherlands.

PURPOSE: The aim of this study was to assess oncologists' practice and attitudes regarding treatment-related infertility and fertility preservation in female cancer patients of reproductive age. PARTICIPANTS AND METHODS: Recruitment letters with a 7-item questionnaire were sent to 454 oncologists. RESULTS: Two hundred and six of the 454 physicians (45%) responded and 96 questionnaires were used for analysis. The sample included 28 (29%) gynaecologists, 22 (23%) medical oncologists, 19 (20%) surgeons, 16 (17%) radiotherapists and 11 (12%) haematologists. Sixty-two percent of the physicians took action to protect ovarian function before or during gonadotoxic therapy. The most important reason for not offering fertility preservation was "factors concerning the disease". About one-third of the oncologists did not discuss fertility issues. Nearly half of the physicians (43%) would offer fertility preservation options, if they were standardized. High importance was given by almost all physicians (96%) to quality of life in general after gonadotoxic therapy and to the provision of information about fertility preservation options (81%). However, when asked about the importance of infertility after a malignancy, a smaller majority of the physicians (59%) gave it high importance. CONCLUSION: Most physicians considered infertility to be a major issue to be discussed, and most intended to take action to protect ovarian function before or during gonadotoxic therapy.

A Delphi consensus study among patients and clinicians in the Netherlands on the procedure of informing young breast cancer patients about Fertility Preservation.

BACKGROUND: The aim of this study was to obtain feedback from, and reach consensus among different experts who are or have been involved in information provision about FP, regarding the (procedure of) information provision about Fertility Preservation (FP) and use of a web-based decision aid (DA) about FP to create optimal conditions for the implementation of the DA-website, as we prepare to implement a DA about FP in the Netherlands. MATERIAL AND METHODS: A two round Delphi study in which experts (patients and clinicians) rated their (dis)agreement with a list of statements (Rounds 1, 2), and additional online forum to discuss dissensus (Round 3). We assessed opinions about FP, web-based DAs, and about the procedure of informing patients. Answer categories ranged from 1 (totally disagree) to 5 (totally agree). Consensus was considered significant when at least 80% of the experts scored either the lowest or the highest two categories. RESULTS: Experts reached rapid consensus on all five statements about the use of a DA (5/5; 100%), and all eight statements about which patients should be offered information about FP (8/8; 100%). However opinions about FP (4/11 statements; 36%), and procedural aspects such as who should inform the patient (6/10 statements; 60%) and when (3/10 statements; 30%) remained for discussion in round 3. In the online discussion some level of agreement was reached for these statements after all. CONCLUSION: It was deemed important that FP options exist. Every eligible patient should receive at least some (general) information about FP, soon after diagnosis. Detailed information should be provided by a fertility expert at a later moment. Exact timing and amount of information should be adjusted to patient's needs and situational context. A DA-website can offer a fair contribution to this.

Timing of fertility preservation procedures in a cohort of female patients with cancer.

OBJECTIVE: Comparison of time intervals from diagnosis to chemotherapy between patients opting for embryo cryopreservation or ovarian tissue cryopreservation. STUDY DESIGN: Retrospective analysis. SETTING: University hospital in the Netherlands. PATIENTS AND METHODS: Thirty-five female patients undergoing fertility preservation procedures before treatment with chemotherapy for cancer. Embryo cryopreservation was performed in 12 patients and ovarian tissue cryopreservation in 23 patients. We investigated differences in time intervals (from diagnosis to start of chemotherapy) between patients opting for embryo cryopreservation and patients opting for ovarian tissue cryopreservation. We calculated time intervals between the moment of diagnosis, the moment of referral, the moment of consultation, the moment of finishing of the fertility preservation procedure and the start of chemotherapy. RESULTS: The median time between diagnosis and referral (median=18 days) and between referral and consultation (median=5 days) was comparable in both groups. A significant difference was found between ovarian tissue cryopreservation and embryo cryopreservation for the time interval between consultation and cryopreservation (p=0.001). Ovarian tissue cryopreservation was completed for half of the patients within 6 days after consultation with the gynecologist, and the hormonal stimulation for embryo cryopreservation was completed for all patients within four weeks (median=18 days), with a median of 11 days of hormonal stimulation. A significant difference was found between ovarian tissue cryopreservation and embryo cryopreservation in the time interval between fertility preservation and start of chemotherapy (median=7 vs 19 days, p=0.019). In sum, the total duration between diagnosis and chemotherapy was significantly shorter for ovarian tissue cryopreservation patients than for embryo cryopreservation patients (median=47 vs 69 days, p=0.042). CONCLUSION: Embryo cryopreservation can be performed within the standard timeframe of cancer care in patients with breast cancer receiving adjuvant chemotherapy, but if delay of the start of chemotherapy is harmful, ovarian tissue cryopreservation can be done within one week.

Female fertility preservation: practical and ethical considerations of an underused procedure.

PURPOSE: Cancer treatments for young women can permanently or temporarily affect fertility. The purpose of this retrospective analysis was to present the clinical experience and ethical considerations of fertility preservation in female oncology patients in a tertiary gynaecological department. METHODS: Since 2002, in 37 patients fertility preservation was performed according to an institutional review board approved protocol in a University hospital in the Netherlands; 33 patients were not treated. RESULTS: Embryo cryopreservation was performed in 10 patients, ovarian tissue cryopreservation in 24, and an ovarian transposition was performed in 3 patients; in one patient combined with an ovarian transplantation and in one patient with ovarian tissue cryopreservation. DISCUSSION: Approved protocols and timing are essential in performing female fertility preservation. Referral for ovarian tissue and embryo cryopreservation is minimal in the Netherlands. Future research focuses on the psychosocial aspects of fertility preservation and explores patients' and professionals' expectations and attitudes regarding fertility preservation and aims to be in line with technical developments.