Fertility preservation for women with breast cancer: a multicentre randomized controlled trial on various ovarian stimulation protocols.

STUDY QUESTION: Does ovarian stimulation with the addition of tamoxifen or letrozole affect the number of cumulus-oocyte complexes (COCs) retrieved compared to standard ovarian stimulation in women with breast cancer who undergo fertility preservation? SUMMARY ANSWER: Alternative ovarian stimulation protocols with tamoxifen or letrozole did not affect the number of COCs retrieved at follicle aspiration in women with breast cancer. WHAT IS KNOWN ALREADY: Alternative ovarian stimulation protocols have been introduced for women with breast cancer who opt for fertility preservation by means of banking of oocytes or embryos. How these ovarian stimulation protocols compare to standard ovarian stimulation in terms of COC yield is unknown. STUDY DESIGN, SIZE, DURATION: This multicentre, open-label randomized controlled superiority trial was carried out in 10 hospitals in the Netherlands and 1 hospital in Belgium between January 2014 and December 2018. We randomly assigned women with breast cancer, aged 18-43 years, who opted for banking of oocytes or embryos to one of three study arms; ovarian stimulation plus tamoxifen, ovarian stimulation plus letrozole or standard ovarian stimulation. Standard ovarian stimulation included GnRH antagonist, recombinant FSH and GnRH agonist trigger. Randomization was performed with a web-based system in a 1:1:1 ratio, stratified for oral contraception usage at start of ovarian stimulation, positive estrogen receptor (ER) status and positive lymph nodes. Patients and caregivers were not blinded to the assigned treatment. The primary outcome was number of COCs retrieved at follicle aspiration. PARTICIPANTS/MATERIALS, SETTING, METHODS: During the study period, 162 women were randomly assigned to one of three interventions. Fifty-four underwent ovarian stimulation plus tamoxifen, 53 ovarian stimulation plus letrozole and 55 standard ovarian stimulation. Analysis was according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: No differences among groups were observed in the mean (±SD) number of COCs retrieved: 12.5 (10.4) after ovarian stimulation plus tamoxifen, 14.2 (9.4) after ovarian stimulation plus letrozole and 13.6 (11.6) after standard ovarian stimulation (mean difference -1.13, 95% CI -5.70 to 3.43 for tamoxifen versus standard ovarian stimulation and 0.58, 95% CI -4.03 to 5.20 for letrozole versus standard ovarian stimulation). After adjusting for oral contraception usage at the start of ovarian stimulation, positive ER status and positive lymph nodes, the mean difference was -1.11 (95% CI -5.58 to 3.35) after ovarian stimulation plus tamoxifen versus standard ovarian stimulation and 0.30 (95% CI -4.19 to 4.78) after ovarian stimulation plus letrozole versus standard ovarian stimulation. There were also no differences in the number of oocytes or embryos banked. There was one serious adverse event after standard ovarian stimulation: one woman was admitted to the hospital because of ovarian hyperstimulation syndrome. LIMITATIONS, REASONS FOR CAUTION: The available literature on which we based our hypothesis, power analysis and sample size calculation was scarce and studies were of low quality. Our study did not have sufficient power to perform subgroup analysis on follicular, luteal or random start of ovarian stimulation. WIDER IMPLICATIONS OF THE FINDINGS: Our study showed that adding tamoxifen or letrozole to a standard ovarian stimulation protocol in women with breast cancer does not impact the effectiveness of fertility preservation and paves the way for high-quality long-term follow-up on breast cancer treatment outcomes and women's future pregnancy outcomes. Our study also highlights the need for high-quality studies for all women opting for fertility preservation, as alternative ovarian stimulation protocols have been introduced to clinical practice without proper evidence. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by a grant (2011.WO23.C129) of 'Stichting Pink Ribbon', a breast cancer fundraising charity organization in the Netherlands. M.G., C.B.L. and R.S. declared that the Center for Reproductive Medicine, Amsterdam UMC (location VUMC) has received unconditional research and educational grants from Guerbet, Merck and Ferring, not related to the presented work. C.B.L. declared a speakers fee for Inmed and Yingming. S.C.L. reports grants and non-financial support from Agendia, grants, non-financial support and other from AstraZeneca, grants from Eurocept-pharmaceuticals, grants and non-financial support from Genentech/Roche and Novartis, grants from Pfizer, grants and non-financial support from Tesaro and Immunomedics, other from Cergentis, IBM, Bayer, and Daiichi-Sankyo, outside the submitted work; In addition, S.C.L. has a patent UN23A01/P-EP pending that is unrelated to the present work. J.M.J.S. reported payments and travel grants from Merck and Ferring. C.C.M.B. reports her role as unpaid president of the National guideline committee on Fertility Preservation in women with cancer. K.F. received unrestricted grants from Merck Serono, Good Life and Ferring not related to present work. K.F. declared paid lectures for Ferring. D.S. declared former employment from Merck Sharp & Dohme (MSD). K.F. declared paid lectures for Ferring. D.S. reports grants from MSD, Gedeon Richter and Ferring paid to his institution; consulting fee payments from MSD and Merck Serono paid to his institution; speaker honoraria from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono paid to his institution. D.S. has also received travel and meeting support from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono. No payments are related to present work. TRIAL REGISTRATION NUMBER: NTR4108. TRIAL REGISTRATION DATE: 6 August 2013. DATE OF FIRST PATIENT'S ENROLMENT: 30 January 2014.

Reproductive outcomes after oocyte banking for fertility preservation.

RESEARCH QUESTION: What are the reproductive outcomes of women who bank oocytes for fertility preservation? DESIGN: A prospective follow-up study of a cohort of 327 women who banked their oocytes for fertility preservation was carried out between July 2009 and August 2015. The indications for oocyte banking and outcomes of ovarian stimulation were collected from medical files. Follow-up data were obtained from an additional questionnaire. RESULTS: In total, 243 out of 327 women (74%) responded and 228 women (70%) consented to participate and returned the questionnaire. The median time to follow-up of these women was 31 months. A total of 101 women (44%) were trying, or had tried, to become pregnant after oocyte banking, of which 66 became pregnant (65%). Five women reported an unintended pregnancy. Of these, 71 women became pregnant, 76% conceived naturally, 7% through intracytoplasmic sperm injection with their vitrified-warmed oocytes and 17% by other medically assisted reproduction treatments. Six women attempted to achieve a pregnancy using their banked oocytes. Of the six pregnancies achieved in five women, two resulted in a live birth. A total of thirty-eight women reported a live birth at the time of follow-up. CONCLUSION: Oocyte banking can be considered a form of risk management or preventive medicine because it is not certain that the women will experience sterility in the future.

[Oocyte vitrification: for whom?]. / Eicelvitrificatie: voor wie eigenlijk? Een dwarsdoorsnede-onderzoek.

OBJECTIVE: To study the indications of oocyte vitrification in women who undergo this intervention. DESIGN: Cross-sectional study. METHOD: We collected the indications of oocyte vitrification in women who underwent, or started ovarian stimulation for, this intervention between May 2006 and December 31st 2013. Indications were subcategorized into six groups: no sperm available during IVF or ICSI treatment, planned gonadotoxic therapy, ovarian surgery, risk on premature ovarian insufficiency , previous gonadotoxic therapy, and anticipated gamete exhaustion. RESULTS: During the study period 298 women vitrified oocytes or started with ovarian stimulation for oocyte vitrification. The majority of the women (33%) vitrified oocytes because of anticipated gamete exhaustion. Planned gonadotoxic treatment was for 81 women (27%) the reason for oocyte vitrification. CONCLUSION: With oocyte vitrification women are able to extend the time at which they can conceive. The future will tell whether the benefits of oocyte vitrification outweigh the risks and costs.

Fertility preservation: a challenge for IVF-clinics.

OBJECTIVE: Acute fertility preservation for women is an interdisciplinary treatment that requires adequate information provision and early referral. This quality management project aimed to improve fertility preservation care by using a practical tool: Strengths, Weaknesses, Opportunities and Threats (SWOT) analysis. STUDY DESIGN: Quality management project was executed between May 2011 and July 2013. This project has been executed in a university affiliated IVF-clinic in cooperation with two oncological sites and used a four-step strategy: (1) monitoring baseline referral process, (2) exploring baseline fertility preservation program by Strengths, Weaknesses, Opportunities and Threats' (SWOT)-analysis, (3) setting up a new fertility preservation program and (4) evaluating the new fertility preservation program by means of SWOT-analysis. RESULTS: During the three-months monitoring period, fertility preservation was requested for a total of 126 women. The mean age of the women was 33.8 years old (range 1-42 years old). Most requests came from women who wanted to cryopreserve oocytes because of age-related decline of fertility (n=90; 71%). Most requests for acute fertility preservation concerned women with breast cancer (n=16; 57%). Information leaflets and pre-consultation questionnaires for women improved the quality of first fertility preservation consultation as evaluated by final SWOT-analysis. Collaboration with oncological centres and information about fertility preservation improved the referral process. CONCLUSIONS: SWOT-analysis proved useful for setting up a new fertility preservation-program and can be recommended as a tool to improve the management and organisation of new types of reproductive care.

Tamoxifen or letrozole versus standard methods for women with estrogen-receptor positive breast cancer undergoing oocyte or embryo cryopreservation in assisted reproduction.

BACKGROUND: Cryopreservation of oocytes or embryos preceded by controlled ovarian stimulation (COS) can increase the chance of future pregnancy in women with breast cancer who risk therapy-induced ovarian failure. In women with estrogen-receptor (ER) positive breast cancer, alternative COS protocols with tamoxifen or letrozole are being used to theoretically inhibit breast cancer growth during COS. OBJECTIVES: To assess the effects of tamoxifen or letrozole, in addition to standard COS protocols, on the breast cancer-free interval in premenopausal women with ER positive breast cancer who undergo COS for embryo or oocyte cryopreservation. SEARCH METHODS: We searched the Ovid Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid EMBASE, Ovid PsycINFO, and EBSCOhost CINAHL. We applied no limitations in year of publication or language. In addition, we searched trial registers for ongoing and registered trials, conference abstracts, and sources of grey literature. The search was conducted in January 2013. SELECTION CRITERIA: Randomised trials comparing different COS protocols in women with breast cancer were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently scanned the titles, abstracts, or both sections according to Cochrane guidelines. If data to include were provided, data extraction would have been independently performed by two review authors by using forms designed according to Cochrane guidelines. MAIN RESULTS: No randomised controlled trials were found that met the inclusion criteria. AUTHORS' CONCLUSIONS: COS schedules with the additional use of tamoxifen or letrozole are commonly chosen as an alternative regimen in young women with ER positive breast cancer who undergo COS for oocyte or embryo cryopreservation. No randomised controlled trials support the idea that these alternative COS schedules are superior to standard COS.

The efficacy of hormonal treatment for residual or recurrent low-grade endometrial stromal sarcoma. A retrospective study.

OBJECTIVE: Low-grade endometrial stromal sarcoma (EES) is a rare tumour with a high recurrence rate but a very good prognosis. Responses to hormonal treatment of these recurrences have been published in case reports. The aim of this study was to determine the objective response rate and response duration of hormonal treatment for recurrent or residual low-grade ESS in a consecutive series of patients. STUDY DESIGN: Thirteen consecutive patients with residual or recurrent disease were retrieved from the files. Eleven patients with measurable disease were treated with hormones and form the basis of this study. The following data were collected: age, date of primary diagnosis, type of primary treatment, the presence and localization of residual or recurrent disease, type of treatment, response, duration of response and survival. RESULTS: After hormonal treatment 9 (82%) patients showed an objective response (4 complete response; 5 partial response), one showed stable disease (26+ months) and one progressive disease. Response duration was from 4+ to 252+ months (median 48+ months). CONCLUSION: Hormonal treatment for measurable residual or recurrent low-grade ESS has a high response rate and should be considered as the treatment of choice for patients in which recurrent disease cannot easily be resected.