Ovarian tissue cryopreservation for fertility preservation in cancer patients: Successful establishment and feasibility of a multidisciplinary collaboration

Background

As advancements in cancer therapies have led to dramatic improvements in long term survival, there has been increasing interest in methods to expand fertility preservation options for cancer patients.

Methods

An experimental protocol for ovarian tissue cryopreservation was developed at the University of Pennsylvania for patients requiring gonadotoxic therapies. The protocol for adults was implemented at the Hospital of the University of Pennsylvania and for children at the Children’s Hospital of Philadelphia in collaboration with the Oncofertility Consortium and the National Physicians Cooperative (NPC).

Results

A total of twenty-one patients (age range: 8–36 years) have cryopreserved ovarian tissue as part of this study. While patients had a variety of diagnoses and treatment exposures, 10/21 (48 %) patients suffered from hematologic disorders and 43 % were anticipating stem cell transplantation. No patients have requested that the tissue be used for clinical purposes.

Conclusions

Ovarian tissue cryopreservation protocols can be implemented at pediatric and adult institutions through multi-disciplinary collaboration. While more research is needed to determine the safety and efficacy of ovarian tissue cryopreservation, this procedure provides hope for preserving the ability to have biological offspring to patients facing gonadotoxic therapies for a variety of medical conditions.     

Recommendations for fertility preservation in patients with lymphomas

Purpose

This guideline aims to serve as a reference for fertility specialists and other specialists working with young patients at risk of premature ovarian insufficiency (POI) or testicular dysfunction (TD) due to treatment of Hodgkin or Non-Hodgkin lymphoma.

Methods

PubMed search of articles addressing risk of POI and TD according to different treatment protocols used in lymphoma patients. PubMed search of articles presenting different options for fertility treatment in cancer patients.

Results

The risk of POI/TD depends on the protocol used with the highest risk in patients treated with haematopoietic stem cell transplantation/bone marrow transplantation (HSCT/BMT) and the lowest risk in patients treated with ABVD (Adriamycin, Bleomycin, Vincristine and Decarbazine). The different options of fertility preservation are discussed and their relevance according to treatment protocol, age of the patient and urgency to start treatment.

Conclusion

Fertility issues should be discussed with all women of fertile age. Fertility preservation should be offered to young women when relevant. Children should be informed together with their parents. All men should be offered semen cryopreservation regardless of protocol used. At present, there are no established methods of fertility preservation in pre-pubertal boys. This guideline offers suggestions to the most preferred methods of fertility preservation according to treatment protocol, age of the patient, and urgency to start treatment.     

Vitrification of embryos and oocytes for fertility preservation in cancer patients

As survival rates and the life expectancy of those with malignancy have increased, more women in their reproductive years are referred for fertility preservation. Chemotherapy and radiotherapy can severely affect ovarian function, and the effect is irreversible. Therefore, it is optimal to attempt fertility preservation before chemotherapy and radiotherapy are initiated. Oocyte and embryo cryopreservation is the most common option for fertility preservation in women. Several reports have proven that embryo and oocyte cryopreservation can achieve a successful pregnancy. This review discusses the impact of chemotherapy and radiotherapy on ovarian function, and the importance of oocyte and embryo cryopreservation for fertility preservation. In addition, the current status of pregnancy outcomes and potential for cryopreserved oocytes to result in live births in cancer patients was reviewed. This may provide useful information for decision‐making in cancer patients regarding oocyte and embryo cryopreservation and fertility preservation.     

Ovarian stimulation and emergency in vitro fertilization for fertility preservation in cancer patients

Objective

To evaluate the outcome of ovarian stimulation and in vitro fertilization (IVF) in women undergoing fertility preservation prior to chemotherapy compared with healthy patients with infertility due to tubal factor.

Study design

Case control, retrospective study in an academic IVF unit. The study participants were 21 cancer patients and 1 patient with focal proliferative glomerulosclerosis, undergoing emergency IVF or intracytoplasmic sperm injection (ICSI; Group A) and 22 patients undergoing IVF for tubal factor (Group B). All patients underwent controlled ovarian stimulation, ovum pick-up, and embryo freezing or transfer. The outcome measures included: dose of gonadotropins, mean estradiol and progesterone levels, length of stimulation, number of retrieved oocytes, number of 2 pronuclei zygotes, fertilization rate, and clinical pregnancy rate. Student's t-test was used for assessment of group comparisons.

Results

Patients in Group A (mean age 32.8 ± 5.7 years) underwent 22 emergency IVF cycles for fertility preservation prior to chemotherapy. The mean number of days until human chorionic gonadotropin administration was 10.4 ± 4.8. Eleven cycles involved normal insemination while nine involved ICSI. In one cycle three arrested immature oocytes were retrieved, and in one cycle no oocytes were retrieved. Donor sperm was used in 9 cycles. Tamoxifen was part of the treatment protocol in 6 IVF cycles of breast cancer patients. The mean age of the women in Group B was 34 ± 4.2 years. There were no significant differences in any of the main outcome measures between the two groups. Thawed embryos were transferred in four cancer patients: two patients had colon cancer, one had breast cancer and one had pseudomyxoma peritonei. Two of these four women conceived and gave birth to healthy newborns.

Conclusions

Emergency IVF is a promising approach for preserving fertility in cancer patients. Current treatment protocols offer a minimal time delay until chemotherapy is commenced, and the ovarian stimulation outcomes are comparable to those of women with tubal factor.     

Female fertility preservation in the pediatric and adolescent cancer patient population

The 5-year survival rate for childhood cancer is over 80%, thereby increasing the number of young women facing infertility in the future because of the gonadotoxic effects of chemotherapy and radiation. The gonadotoxic effects of childhood cancer treatment vary by the radiation regimen and the chemotherapeutic drugs utilized. Although the American Society of Clinical Oncology guidelines recommend fertility preservation for all patients, there are several barriers and ethical considerations to fertility preservation in the pediatric and adolescent female population. Additionally, the fertility preservation methods for pre- and postpubertal females differ, with only experimental methods available for prepubertal females. We will review the risk of chemotherapy and radiation on female fertility, the approach to fertility preservation in the pediatric and adolescent female population, methods of fertility preservation for both pre- and postpubertal females, barriers to fertility preservation, cost, and psychological and ethical considerations.     

Oocyte cryopreservation: a feasible fertility preservation option for reproductive age cancer survivors

Purpose  

To compare oocyte cryopreservation cycles performed in cancer patients to those of infertile women.     

Fifteen year follow-up of embryos cryopreserved in cancer patients for fertility preservation

Purpose

Determine the outcome of embryo cryopreservation in female oncology patients

Methods

The outcomes of IVF/ICSI cycles in oncology patients over 15 years in a University Teaching Hospital.

Results

Forty-two oncology patients (mean 31.9 ± 3.9 years) underwent embryo cryopreservation treatment (n = 33 IVF, n = 6 ICSI). Controlled ovarian stimulation with GnRH antagonist protocol (n = 34; 81 %) yielded fewer oocytes than GnRH agonist protocol (n = 8; 19 %) (9.4 ± 6.3 vs. 15.3 ± 8.9; p = 0.04) respectively. There was no significant difference in mean (±SD) duration of ovarian stimulation (11.6 ± 2.6 vs.10.6 ± 2.7), median gonadotrophin dose (1950 vs. 1670 IU), median day 5–6 oestradiol level (1124 vs.1129 pmol/l) or embryo yield (6.2 ± 4.1 vs. 8.8 ± 4.3; p = 0.07) between GnRH antagonist and agonist treatment cycles respectively. Thirty-nine patients cryopreserved embryos and three had their cycle cancelled. During this study period, of those who cryopreserved embryos, 5 patients underwent 9 frozen-thaw cycles (13 %), resulting in 2 live births (1 twin, 1 singleton, live birth rate 22 %). Six patients died (15 %), 3 conceived naturally (8 %) and 2 couples separated (5 %). Fourteen patients discarded their embryos (36 %). Twenty-two patients’ (56 %) have embryos remaining in storage.

Conclusions

This study demonstrates that embryo cryopreservation in female oncology patients gives a satisfactory live birth rate. However, there are concerns regarding cost-effectiveness, resulting from high disposal/non-usage of embryos, and further studies are required.     

Results from the survey for preservation of adolescent reproduction (SPARE) study: gender disparity in delivery of fertility preservation message to adolescents with cancer

Purpose  

Diminished reproductive capacity is a devastating consequence of life-sparing therapies for childhood malignancy. In 2006, the American Society of Clinical Oncology (ASCO) published fertility preservation recommendations (ASCOR) emphasizing the importance of early discussion and intervention for fertility preservation strategies. Using the Survey for Preservation of Adolescent REproduction (SPARE), we sought to determine fertility preservation attitudes and practice patterns post-ASCOR from pediatric oncology specialists nationwide.     

Pronuclear embryo cryopreservation experience: outcomes for reducing the risk of ovarian hyperstimulation syndrome and for fertility preservation in cancer patients

Purpose  

To evaluate pregnancy rate (PR) and live birth rate (LBR) after freezing pronuclear (PN) embryos for two purposes: to reduce the risk of ovarian hyperstimulation syndrome (OHSS) and to bank embryos for cancer patients anticipating gametotoxic chemotherapy/radiotherapy.     

Ovarian stimulation and in-vitro fertilization outcomes of cancer patients undergoing fertility preservation compared to age matched controls: a 17-year experience

Purpose

To compare the in-vitro fertilization (IVF) outcomes of cancer patients who underwent oocyte retrieval and embryo/oocyte cryopreservation prior to gonadotoxic therapy to those of age and time-matched controls with tubal factor infertility.

Methods

All cancer patients who underwent embryo/oocyte cryopreservation at our institution from 1997 to 2014 were reviewed. Primary outcomes were total dose of gonadotropins used, number of oocytes retrieved, and number of 2pn embryos obtained. Outcomes were compared to age-matched controls with tubal-factor infertility who underwent a fresh embryo transfer within the same relative time period as the IVF cycle of the cancer patient.

Results

Sixty-three cancer patients underwent 65 IVF cycles, and 21 returned for frozen embryo transfer. One hundred twenty-two age-matched controls underwent IVF cycles with fresh transfer, and 23 returned for frozen embryo transfer. No difference was seen between cancer patients and controls with respect to total ampules of gonadotropin used (38.0 vs. 35.6 respectively; p = 0.28), number of oocytes retrieved (12.4 vs. 10.9 respectively; p = 0.36) and number of 2pn embryos obtained (6.6 vs. 7.1 respectively; p = 0.11). Cumulative pregnancy rate per transfer for cancer patients compared to controls was 37 vs. 43 % respectively (p = 0.49) and cumulative live birth rate per transfer was 30 vs. 32 % respectively (p = 0.85). Cancer patients had a higher likelihood of live birth resulting in twins (44 vs. 14 %; p = 0.035).

Conclusions

Most IVF outcomes appear comparable for cancer patients and age-matched controls. Higher twin pregnancy rates in cancer patients may reflect lack of underlying infertility or need for cancer-specific transfer guidelines.     

Applicability of adult techniques for ovarian preservation to childhood cancer patients

Purpose

To appraise the feasibility of current adult medical and surgical techniques for ovarian preservation in pre-pubertal and adolescent girls with cancer.

Methods

Literature search using PubMed and SCOPUS up to February 2012. In addition, the reference lists of selected studies and all identified systematic and narrative reviews were scanned for relevant references. Inclusion criteria were ovarian preservation and cancer. Exclusion criteria were non-English publications, letters, personal communications, and ovarian preservation for conditions other than cancer.

Results

Data from the selected publications was interpreted and discussed in the relevant sections. Cryopreservation of ovarian tissue followed by autologous transplant represents the only surgical option available for pre-pubertal girls and adolescents who cannot delay the start of chemotherapy. Few studies report on pre-pubertal and adolescent girls undergoing ovarian preservation surgeries with good harvesting, and no follow-up has been conveyed, to date. Outcomes of ovarian function after ovarian suppression with GnRH-analogs in adults have been controversial and no reports are available for pre-pubertal girls.

Conclusions

Autologous transplantation of cryopreserved ovarian cortex probably represents the best option for preservation of fertility and hormonal function in childhood cancer females; however, future research needs to address the safety of this technique, especially in patients with blood-borne cancers. Ovarian suppression with GnRH-analogs at the time of chemotherapy treatment has not proven to be superior to non-suppression for fertility preservation purposes in adults. Not enough evidence is presently available in childhood cancer patients.     

Fertility preservation among young breast cancer patients: A single-center experience in China

ObjectiveThis study aims to investigate the status of fertility preservation (FP) in young breast cancer patients.Materials and methodsA clinical database of six women with breast cancer who wished to undergo FP before starting chemotherapy were analyzed between January 2018 and December 2019 in our hospital. Among the six women, three were unmarried and three were married.ResultsThree patients chose oocyte preservation and obtained 23, 7, and 17 MII oocytes, respectively. One patient chose embryo freezing, and three embryos were frozen. Fertility preservation failed for two patients, one of whom had premature ovulation, while the other patient abandoned egg retrieval on the human chorionic gonadotropin (HCG) day.ConclusionThe present results indicate that oocyte and embryo cryopreservation are effective optional methods for young breast cancer patients. However, a lack of knowledge, the urgency of cancer treatment, and financial constraints are causes for a low access rate regarding this process.     

A synopsis of global frontiers in fertility preservation

Since 2007, the Oncofertility Consortium Annual Conference has brought together a diverse network of individuals from a wide range of backgrounds and professional levels to disseminate emerging basic and clinical research findings in fertility preservation. This network also developed enduring educational materials to accelerate the pace and quality of field-wide scientific communication. Between 2007 and 2019, the Oncofertility Consortium Annual Conference was held as an in-person event in Chicago, IL. The conference attracted approximately 250 attendees each year representing 20 countries around the world. In 2020, however, the COVID-19 pandemic disrupted this paradigm and precluded an in-person meeting. Nevertheless, there remained an undeniable demand for the oncofertility community to convene. To maintain the momentum of the field, the Oncofertility Consortium hosted a day-long virtual meeting on March 5, 2021, with the theme of “Oncofertility Around the Globe” to highlight the diversity of clinical care and translational research that is ongoing around the world in this discipline. This virtual meeting was hosted using the vFairs ® conference platform and allowed over 700 people to participate, many of whom were first-time conference attendees. The agenda featured concurrent sessions from presenters in six continents which provided attendees a complete overview of the field and furthered our mission to create a global community of oncofertility practice. This paper provides a synopsis of talks delivered at this event and highlights the new advances and frontiers in the fields of oncofertility and fertility preservation around the globe from clinical practice and patient-centered efforts to translational research.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10815-022-02570-5.     

Setting up a fertility preservation programme

With improved survival rates from cancer, young people can expect to lead a normal life, including having their own children. However, cancer or other serious disease itself, and more often its treatment, often leads to a significant reduction in fertility or premature gonadal insufficiency. There is increasing acknowledgement for the importance of fertility preservation (FP) options to be discussed and offered to young people whose fertility is at risk, ideally before the gonadotoxic therapy begins. FP options currently include oocyte, embryo and ovarian tissue cryopreservation; ovarian protection during chemotherapy and semen, sperm and testicular tissue cryopreservation. A multidisciplinary team consisting of committed and enthusiastic doctors, scientists, nurses, counsellors, administrators and researchers is required to provide a holistic FP service with rapid response capacity for acute consultation and procedures and a robust system for long-term follow-up. This speciality is developing rapidly with exciting scientific advances that have relevance for the whole spectrum of reproductive medicine.     

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.     

The effect of cancer treatment on female fertility and strategies for preserving fertility

Aggressive chemotherapy and radiotherapy in young patients with cancer has greatly enhanced the life expectancy of these patients, but these treatments often cause infertility because of the massive destruction of the ovarian reserve resulting in premature ovarian failure (POF). This review focuses on the effect of cancer treatments on fertility and on the various surgical and assisted-reproduction innovations that are available to provide the patient with the option of future pregnancies. As the emerging discipline of fertility preservation is steadily attracting increasing interest, developments in the near future promise to be very exciting. However, in everyday routine work, better interdisciplinary cooperation between gynecological and pediatric oncologists, surgeons, immunologists and endocrinologists is necessary so that individualized options for fertility preservation can be offered in advance of surgical procedures or cancer treatments. GnRH analog treatment can preserve fertility in some patients, but not in all. At present, cryopreservation of ovarian tissue appears as a very promising method of providing the cancer patient with a realistic chance of preserving fertility—a prospect that is also extremely important to patients for psychological reasons.     

Aspects cliniques pratiques de la vitrification ovocytaire en oncofertilité

Oocyte vitrification is a preservation fertility strategy, which can be performed in women after puberty to preserve gametes before beginning a gonadotoxic anticancer treatment. Based on available literature and our personal data, we aim to provide an overview about the feasibility, the clinical and logistic difficulties of oocyte vitrification in the field of oncofertility: limit age for oocyte cryopreservation, time required and protocols for ovarian controlled stimulation, ovarian response to stimulation, for what hopes of pregnancy?