Introduction

Several malignancies occur at a young age and may necessitate aggressive anticancer therapies including alkylating chemotherapy and ionizing radiation that could lead to gonadotoxicity and subsequent fertility loss as a devastating side effect. According to the most recent international guidelines of the American Society of Clinical Oncology (ASCO) and the American Society for Reproductive Medicine (ASRM), several established, debatable, and experimental oncofertility options can be offered to young female and male patients with cancer to preserve and restore fertility [1, 2]. Established oncofertility options include sperm freezing, embryo freezing, egg freezing, and recently ovarian tissue freezing and autotransplantation. Debatable oncofertility options include GnRH analogs and hormonal suppression, oophoropexy, gonadal shielding, and fractionation of chemotherapy and radiotherapy. Experimental oncofertility options include oocytes in vitro maturation (IVM), artificial ovary, testicular tissue freezing and autotransplantation, in vitro spermatogenesis, neoadjuvant cytoprotective pharmacotherapy, and stem cell reproductive technology.

However, such oncofertility international guidelines face several challenges in practice. Over the past years, the Oncofertility Consortium has studied oncofertility practice in many countries within its Oncofertility Professional Engagement Network (OPEN). Our previous studies identified a variety of standards in oncofertility practice around the globe due to limited resource settings, shortage of reproductive care services provided to young patients with cancer, lack of awareness among providers and patients, cultural and religious constraints, lack of insurance coverage, high out-of-pocket costs for patients, and lack of funding to support oncofertility programs [3,4,5,6,7,8,9]. Despite these challenges, many opportunities exist and create a significant potential for the future including improved cancer survival rates and improved success rates of many oncofertility options as well as emergence of new promising technologies. Therefore as a practical approach, the Oncofertility Consortium recommends installation of specific oncofertility programs for common cancers such as childhood, breast, and blood cancers according to the contemporary challenges and opportunities. This practical approach will provide efficient oncofertility edification and modeling to oncofertility teams and related healthcare providers around the globe and help them offer the best care possible to their patients. To carry out this practical approach, the Oncofertility Consortium has designed its new Repro-Can-OPEN Studies (Reproduction and Cancer in the Oncofertility Professional Engagement Network).

Recently in our Repro-Can-OPEN Study Part 1 published at Journal of Assisted Reproduction and Genetics (JARG) [10], we proposed installation of specific oncofertility programs for common cancers in limited resource settings amidst a current global crisis of the COVID-19 pandemic as well as in 14 developing countries from Africa, Asia, and Latin America. As a further step to reflect the actual wide spectrum of oncofertility practice around the globe and to help provide plausible oncofertility best practice models, we propose here in our Repro-Can-OPEN Study Part 2 installation of specific oncofertility programs for common cancers in optimum resource settings. Our Repro-Can-OPEN Study Part 2 is based on the practical experience of 25 leading and well-resourced oncofertility centers and institutions from the USA, Europe, Australia, and Japan.

Methods

The Oncofertility Consortium sent the Repro-Can-OPEN Study Part 2 questionnaire via email to 25 leading and well-resourced oncofertility centers and institutions from the USA, Europe, Australia, and Japan (Table 1 and Fig. 1) to be proposed for childhood cancer, breast cancer, and blood cancer. The Repro-Can-OPEN Study Part 2 questionnaire included questions on the availability of fertility preservation options provided to young female and male patients with cancer and whether these options are always, commonly, occasionally, or rarely used. The responses for childhood cancer, breast cancer, and blood cancer from the surveyed centers were collected, reviewed, and analyzed.

Table 1 Surveyed oncofertility centers
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Fig. 1
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Merger of American and global networks into one unified network, the Oncofertility Professional Engagement Network (OPEN)

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To analyze the collected data, our coauthor Dr. Salama from Northwestern University developed the new scoring system “oncofertility score”. As previously described [10], the oncofertility score is a new diagnostic tool to measure the availability and utilization of oncofertility options for cancer patients in a treating center, country, or group of centers or countries. It is also a prognostic tool to follow up on the development of oncofertility options and strategies provided to cancer patients over time. The oncofertility score is calculated as a percentile ratio between the actual and maximal points of utilization that an oncofertility option might have (Table 2 and Fig. 2). When a fertility preservation option is available and always used for cancer patients, it is given (Yes ++++) that weighs 100 actual points (25 points per each +). When a fertility preservation option is available and commonly used for cancer patients, it is given (Yes +++) that weighs 75 actual points (25 points per each +). When a fertility preservation option is available but occasionally used for cancer patients, it is given (Yes ++) that weighs 50 actual points (25 points per each +). When a fertility preservation option is available but rarely used or only used in research settings for cancer patients, it is given (Yes +) that weighs 25 actual points (25 points per each +). When a fertility preservation option is not available, it is given (No) that weighs 0 actual points. When the fertility preservation option is not available to cancer patients because it is still in the preclinical research stage, it is marked with (No*). The maximal point of utilization that an oncofertility option might have is 100 when it is available and always used for cancer patients and is given (Yes ++++) (25 points per each +).

Table 2 Oncofertility score calculation
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Fig. 2
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Oncofertility score calculation

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In this study of 25 surveyed centers, the oncofertility score is calculated as a percentile ratio between the total actual points and the total maximal points of utilization that an oncofertility option might have. The total actual points for an oncofertility option equal the sum of actual points for this option in all 25 surveyed centers. The total maximal points for an oncofertility option equal 100 points multiplied by 25 (number of surveyed centers in this study) resulting in 2500 points.

Results

All 25 surveyed centers responded to all questions. Each surveyed center has the same serial number in all tables (Tables 1, 3, 4, and 5). Responses for childhood, breast, and blood cancers and their calculated oncofertility scores are listed in Tables 3, 4, and 5.

Table 3 Oncofertility options and scores (%) for childhood cancer in all 25 surveyed centers
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Table 4 Oncofertility options and scores (%) for breast cancer in all 25 surveyed centers
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Table 5 Oncofertility options and scores (%) for blood cancer in all 25 surveyed centers
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The oncofertility scores for options provided to children with cancer in all 25 surveyed centers were as follows: gonadal shielding in case of irradiation (69%), ovarian tissue freezing (63%), fractionation of chemo- and radiotherapy (61%), oophoropexy in case of pelvic irradiation (42%), testicular tissue freezing (41%), GnRH analogs in case of old child (9-14 years) (35%), oocyte in vitro maturation (IVM) (18%), neoadjuvant cytoprotective pharmacotherapy (6%), artificial ovary (2%), in vitro spermatogenesis (2%), and stem cells (0%) (Table 3 and Fig. 3).

Fig. 3
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Oncofertility options and scores (%) for childhood cancer in all 25 surveyed centers

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The oncofertility scores for options provided to female patients with breast cancer in all 25 surveyed centers were as follows: egg freezing (77%), IVF/ICSI of frozen oocytes (75%), gonadal shielding in case of irradiation (75%), embryo freezing (66%), frozen embryo transfer (64%), fractionation of chemo- and radiotherapy (62%), GnRH analogs (61%), ovarian tissue freezing (49%), autotransplantation of frozen ovarian tissue (43%), oocyte in vitro maturation (IVM) (23%), neoadjuvant cytoprotective pharmacotherapy (5%), artificial ovary (2%), and stem cells (0%) (Table 4 and Fig. 4).

Fig. 4
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Oncofertility options and scores (%) for breast cancer in all 25 surveyed centers

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The oncofertility scores for options provided to patients with blood cancer in all 25 surveyed centers were as follows: sperm freezing (83%), gonadal shielding in case of irradiation (75%), egg freezing (68%), fractionation of chemo- and radiotherapy (62%), embryo freezing (58%), ovarian tissue freezing (57%), GnRH analogs (57%), oophoropexy in case of pelvic irradiation (46%), testicular tissue freezing (38%), oocyte in vitro maturation (IVM) (23%), neoadjuvant cytoprotective pharmacotherapy (7%), artificial ovary (2%), in vitro spermatogenesis (2%), and stem cells (0%) (Table 5 and Fig. 5).

Fig. 5
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Oncofertility options and scores (%) for blood cancer in all 25 surveyed centers

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Discussion

In our Repro-Can-OPEN Study Part 2, the responses and their calculated oncofertility scores (Tables 3, 4, and 5 and Figs. 3, 4, and 5) showed three major characteristics of oncofertility practice in optimum resource settings: (1) strong utilization of sperm freezing, egg freezing, embryo freezing, ovarian tissue freezing, gonadal shielding, and fractionation of chemo- and radiotherapy; (2) promising utilization of GnRH analogs, oophoropexy, testicular tissue freezing, and oocyte in vitro maturation (IVM); and (3) rare utilization of neoadjuvant cytoprotective pharmacotherapy, artificial ovary, in vitro spermatogenesis, and stem cell reproductive technology as they are still in preclinical or early clinical research settings.

Proper technical and ethical concerns should be considered when offering advanced and experimental oncofertility options to patients including gonadal tissue freezing and autotransplantation, in vitro maturation of gametes, artificial gonad technology, neoadjuvant cytoprotective pharmacotherapy, and stem cell reproductive technology. Technically, the aforementioned advanced oncofertility options are sophisticated procedures that require well-resourced oncofertility centers with expert teams of oncologists, reproductive endocrinology and infertility specialists, pediatric and adolescent gynecologists, urologists, pediatric endocrinologists, biologists, embryologists, scientists, and transplantation surgeons. That is why they should be performed only at highly specialized oncofertility centers in optimum resource settings. Early referral of cancer patients to such highly specialized oncofertility centers is strongly recommended. Ethically, most of these advanced oncofertility options are experimental or have limited data on efficacy, and it is essential that they are offered to patients under clear ethical regulations. Special ethical and legal considerations need to be considered in children [11, 12]. Obtaining ethical approval from the Institutional Review Board (IRB) or the equivalent ethics committee is essential, as is obtaining informed consent from the patients or the legal guardians in the case of a minor. Informed consent for experimental medical treatments and interventions should include the explanation of the procedures, benefits, risks, alternative treatments, and information about the expected outcome and costs. Several oncofertility options are expensive and not fully covered by health insurance in some states and countries, leaving many patients under critical financial pressure. In such complex situations, doctors and patient navigators as well as patient support and advocacy organizations can play an important role in reassuring and guiding patients or legal guardians of minors during counseling [13,14,15,16,17,18].

Installing oncofertility programs in optimum resource settings

Based on the responses and their calculated oncofertility scores (Tables 3, 4, and 5 and Figs. 3, 4, and 5), we will try here to tailor and install plausible oncofertility programs for common cancers in optimum resource settings as an extrapolation for best practice models (Table 6). Previous international oncofertility guidelines and recommendations were considered as well [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35]. Immediately after cancer diagnosis, we recommend early referrals of patients to oncofertility specialists to check the anticancer therapy plan and estimate the related risk of gonadotoxicity and subsequent fertility loss. The risk of anticancer therapy-induced gonadotoxicity and fertility loss depends mainly on the type and stage of the disease, type and dose of anticancer therapy, and the age of the patient at the time of treatment. If the risk of gonadotoxicity and fertility loss is detected or even unknown, a comprehensive multidisciplinary oncofertility strategy should be offered before, during, and after anticancer therapy.

Table 6 Suggested best practice models: plausible fertility preservation and restoration strategies for cancer patients
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From a practical point of view, an effective oncofertility strategy should be individualized and tailored to the patient’s circumstances and it may integrate various established, debatable, and experimental options after proper counseling and obtaining informed consent from the patient or the legal guardians of a minor. It is recommended that the proposed oncofertility strategy should include at least one cryopreservation option. After complete cure from cancer, and when the patient decides to have biological children, a new assessment of reproductive functions should be performed. If anticancer therapy-induced gonadal dysfunction exists, fertility restoration may be achieved by using the cryopreserved gametes or gonadal tissue.

Installing oncofertility programs for childhood cancer in optimum resource settings

The common forms of childhood cancers that may require aggressive gonadotoxic anticancer therapy and hence necessitate prior fertility preservation measures are leukemia, central nervous system cancers, lymphoma, and sarcomas. Unique medical challenges in oncofertility programs for childhood cancer exist and include the following: (1) freezing of gonadal tissues is the only suitable cryopreservation option before puberty, and (2) autotransplantation of frozen gonadal tissue may carry the risk of reintroducing malignant cells, especially in leukemia which is the most common childhood cancer [36,37,38,39,40,41,42].

According to the aforementioned unique medical challenges, as well as the responses and their calculated oncofertility scores (Table 3 and Fig. 3), we suggest installing the following oncofertility programs for childhood cancer in optimum resource settings. Before initiation of anticancer therapy, freezing of prepubertal gonadal tissues (ovarian or testicular tissue) should be encouraged and attempted when possible. In vitro maturation and further vitrification of gametes (oocytes or spermatozoa) and artificial gonad technology (ovary or testis) are still experimental and cannot be relied upon as effective oncofertility options in children. Although experimental, these emerging technologies of in vitro maturation of gametes and artificial gonads aim to provide safe alternatives to avoid future gonadal tissue autotransplantation and potential reintroduction of malignant cells. Oophoropexy before female pelvis irradiation should be attempted when possible. During anticancer therapy, gonadal shielding in case of irradiation should be attempted. Fractionation of chemo- and radiotherapy could be attempted whenever deemed feasible by the oncologists. Use of GnRH analogs to preserve fertility during chemotherapy in case of older children (9-14 years) is widely debated and needs more research to inform evidence-based practice. Neoadjuvant cytoprotective pharmacotherapy is still experimental and not yet clinically proven as an effective oncofertility option. After anticancer therapy, gonadal function should be monitored to ensure appropriate growth, pubertal development, and reproductive function, with hormone replacement introduced in those with gonadal failure. Furthermore, regular follow-up in survivorship offers a window of opportunity for interval fertility and sexual healthcare, linking patients in with the tissue storage laboratory, and discussing expectations around relationships, pregnancy, and parenthood [43]. When the patient becomes an adult and wishes to have children, fertility restoration may be possible using stored gonadal tissue or gametes. Autotransplantation of gonadal tissue can be offered to restore fertility but it should be handled with caution in patients with leukemia due to possible contamination of gonadal tissue with leukemic cells. According to few reports, harvesting gonadal tissue after the first cycles of anticancer therapy and during complete remission followed by proper gonadal tissue assessment for minimal residual disease (MRD) may reduce the risk of reintroducing leukemic cells with autotransplantation [44, 45]. For additional safety measures, it may be a possible option for patients with leukemia to remove the transplanted gonadal tissue later after restoring fertility and having biological children [46, 47]. Stem cell reproductive technology may be promising in research settings but it is not yet clinically proven as an effective oncofertility option (Table 6).

Installing oncofertility programs for breast cancer in optimum resource settings

Breast cancer is the most common cancer in women during their reproductive years. Breast cancer may require aggressive gonadotoxic anticancer therapy and hence necessitate prior fertility preservation measures. Women with BRCA1 or BRCA2 mutations carry significantly higher risks to develop breast and ovarian cancers (hereditary breast-ovarian cancer syndrome; HBOC), and they should receive appropriate oncofertility care as well. According to a recent large study, the cumulative breast cancer risk is 72% for BRCA1 and 69% for BRCA2 carriers, while the cumulative ovarian cancer risk is 44% for BRCA1 and 17% for BRCA2 carriers [48]. Unique medical challenges in oncofertility programs for breast cancer exist and include the following: (1) conventional ovarian stimulation prior to egg or embryo freezing results in elevated serum estradiol levels that should be avoided in estrogen sensitive malignancies such as breast cancer, and (2) autotransplantation of frozen ovarian tissue in patients with BRCA mutations should be handled with caution due to significantly higher risks of developing ovarian cancer [49,50,51,52,53].

According to the aforementioned unique medical challenges as well as the responses and their calculated oncofertility scores (Table 4 and Fig. 4), we suggest installing the following oncofertility programs for breast cancer in optimum resource settings. Before initiation of anticancer therapy, freezing of eggs or embryos should be attempted with a random-start protocol for controlled ovarian stimulation and using letrozole or tamoxifen to avoid high estradiol levels. Freezing of ovarian tissue should be attempted when possible. In vitro maturation and further vitrification of oocytes retrieved in vivo or ex vivo from the extracted ovarian tissue (ovarian tissue oocytes in vitro maturation; OTO-IVM) could be attempted [54,55,56]. Artificial ovary technology is still experimental and cannot be relied upon alone as an effective oncofertility option. Although experimental, oocyte IVM and artificial ovary technology aim to provide safe alternatives to avoid future ovarian tissue autotransplantation and potential reintroduction of malignant cells. During anticancer therapy, GnRH analog administration before and during chemotherapy can be considered. Fractionation of chemo- and radiotherapy could be attempted whenever deemed feasible by the oncologists. Gonadal shielding might be needed in case of combined irradiation to ovaries. Neoadjuvant cytoprotective pharmacotherapy is still experimental and not yet clinically proven as an effective oncofertility option. After anticancer therapy, fertility restoration may be achieved by frozen embryo transfer, or in vitro fertilization of stored oocytes. Patients with BRCA mutations could be advised to use preimplantation genetic testing (PGT) during in vitro fertilization to avoid transmitting the mutation. Autotransplantation of frozen ovarian tissue can be offered to restore fertility but it should be handled with caution in patients with BRCA mutations due to significantly higher risks of developing ovarian cancer. Proper ovarian tissue assessment in patients with BRCA mutations is mandatory to reduce the risk of reintroducing malignant cells with autotransplantation. For additional safety measures, it may be a possible option for patients with BRCA mutations to remove the transplanted ovarian tissue as well as the remaining ovary (if any) after childbearing is complete and at the time of an elective caesarian section. Stem cell reproductive technology may be promising in research settings but it is not yet clinically proven as an effective oncofertility option (Table 6).

Installing oncofertility programs for blood cancer in optimum resource settings

The common forms of blood cancers that occur during the reproductive age and may require immediate aggressive gonadotoxic anticancer therapy and hence necessitate prior fertility preservation measures are acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL). Unique medical challenges in oncofertility programs for blood cancer exist and include the following: (1) most cases of blood cancer especially leukemia necessitate immediate initiation of anticancer therapy leaving very short time to offer fertility preservation options, thus may be precluded by the health status of the patient and the time available, and (2) autotransplantation of frozen gonadal tissue may carry the risk of reintroducing malignant cells, especially in leukemia [57,58,59].

According to the aforementioned unique medical challenges as well as the responses and their calculated oncofertility scores (Table 5 and Fig. 5), we suggest installing the following oncofertility programs for blood cancer in optimum resource settings. Before initiation of anticancer therapy, freezing of embryos or gametes (oocytes or spermatozoa) should be attempted when possible. Freezing of gonadal tissues (ovarian or testicular tissue) should be attempted after proper tissue assessment to exclude contamination with malignant cells. In vitro maturation and further vitrification of gametes retrieved in vivo or ex vivo from the extracted gonadal tissue could be attempted. Artificial gonad technology is still experimental and cannot be relied upon alone as an effective oncofertility option. Although experimental, these emerging technologies of in vitro maturation of gametes and artificial gonads aim to provide safe alternatives to avoid future gonadal tissue autotransplantation and potential reintroduction of malignant cells. Oophoropexy before female pelvis irradiation should be attempted when possible. During anticancer therapy, gonadal shielding in case of irradiation should be attempted. Fractionation of chemo- and radiotherapy could be attempted whenever deemed feasible by the oncologists. Use of GnRH analogs to preserve fertility during chemotherapy in case of hematological malignancies is widely debated and needs more research to inform evidence-based practice. Neoadjuvant cytoprotective pharmacotherapy is still experimental and not yet clinically proven as an effective oncofertility option. After anticancer therapy, fertility restoration may be achieved by frozen embryo transfer, or in vitro fertilization of stored gametes. Autotransplantation of frozen gonadal tissue can be offered to restore fertility but it should be handled with caution in patients with leukemia due to possible contamination of gonadal tissue with leukemic cells. According to a few reports, harvesting gonadal tissue after the first cycles of anticancer therapy and during complete remission followed by proper gonadal tissue assessment for minimal residual disease (MRD) may reduce the risk of reintroducing leukemic cells with autotransplantation. For additional safety measures, it may be a possible option for patients with leukemia to remove the transplanted gonadal tissue later after restoring fertility and having biological children [46, 47]. Stem cell reproductive technology may be promising in research settings but it is not yet clinically proven as an effective oncofertility option (Table 6).

After installation of these specific oncofertility programs for common cancers in optimum resource settings, we encourage using the “oncofertility score” as a prognostic tool to follow up on the development of these new oncofertility programs over time.

In cases where oncofertility options are rejected, contraindicated, infeasible, unsuccessful, or unavailable, adoption and third-party reproduction, such as sperm, egg, and embryo donation and surrogacy, can be offered as family building alternatives.

Next steps and future directions of Repro-Can-OPEN Studies

In our next Repro-Can-OPEN studies, we are planning to investigate in detail the oncofertility programs offered to leukemia and lymphoma patients according to their gender and age group. We are planning also to investigate other cancers as well as other patient groups (e.g., LGBTQ population: lesbian, gay, bisexual, transgender, and queer or questioning) who were not included in our previous studies. We will provide further discussions on the advanced and the emerging oncofertility options, and highlight the recent achievements in the related preclinical research [60,61,62,63,64,65]. The Oncofertility Consortium will continue to engage more stakeholders from the USA and abroad to help build a sustainable oncofertility core competency worldwide.

Conclusion

Our Repro-Can-OPEN Study Part 2 proposed installing specific oncofertility programs for common cancers in optimum resource settings as an extrapolation for best practice models. Responses for childhood, breast, and blood cancers and their calculated oncofertility scores showed three major characteristics of oncofertility practice in optimum resource settings: (1) strong utilization of sperm freezing, egg freezing, embryo freezing, ovarian tissue freezing, gonadal shielding, and fractionation of chemo- and radiotherapy; (2) promising utilization of GnRH analogs, oophoropexy, testicular tissue freezing, and oocyte in vitro maturation (IVM); and (3) rare utilization of neoadjuvant cytoprotective pharmacotherapy, artificial ovary, in vitro spermatogenesis, and stem cell reproductive technology as they are still in preclinical or early clinical research settings. Proper technical and ethical concerns should be considered when offering advanced and experimental oncofertility options to patients. Dissemination of our study results and recommendations will provide efficient oncofertility edification and modeling to oncofertility teams and related healthcare providers around the globe and help them offer the best care possible to their patients.