Exploring Pediatric Oncofertility: Challenges and Advances in Cancer Treatment and Fertility Preservation

Oncofertility, a field that focuses on the potential impact of cancer treatments on future fertility, is relatively new and especially complex in pediatric cases. This complexity arises from unique considerations like consent and ethical issues when dealing with children. Despite the variety in childhood cancer treatments and outcomes, the overall survival rate is now over 80%, leading to a significant number of survivors facing long-term effects of treatment, including infertility. The gonads are particularly vulnerable to cancer treatments, with data indicating a higher risk of infertility in males compared to females among childhood cancer survivors.

Infertility can result from various cancer treatments, such as certain types of chemotherapy, notably those involving alkylating agents and heavy metals, and radiation therapy. The latter can directly impact the gonads or indirectly affect fertility through the brain’s hypothalamic and pituitary secretion of gonadotropins. Furthermore, surgical interventions that involve removing reproductive organs also contribute to infertility.

With the recognized risk of infertility, especially in high-risk patients, the practice of preserving sex cells or gonadal tissue for future fertility treatments is well-established. Guidelines recommend referral for fertility preservation services to all eligible post-pubertal patients. The authors recently reviewed current advancements in pediatric oncofertility and will discuss both the scope of this issue and recent developments in delivering oncofertility care to pediatric patients. Childhood and adolescent cancer, though relatively rare, affects thousands annually in the United States, with common types including leukemias, lymphomas, and central nervous system tumors.

Advancements and Challenges in Pediatric Fertility Preservation:

In pediatric fertility preservation (FP), significant strides have been made, particularly for post-pubertal patients. Protocols involving gonadal tissue or sex cells have successfully resulted in live births post-cancer treatment. Notably, there has been a breakthrough with a post-menarche patient experiencing primary ovarian failure, who achieved pregnancy and a live birth through reimplanted, cryopreserved ovarian tissue. Additionally, a mature oocyte was derived from the cryopreserved ovarian tissue of a 6-year-old, indicating potential clinical success for pre-pubertal females soon.

Contrastingly, progress in pre-pubertal males remains challenging. Successful maturation of spermatogonial stem cells from pre-pubertal human tissue hasn’t been achieved. In vitro maturation of testicular stem cells is another area under exploration. While the differentiation of these cells into mature sperm hasn’t been accomplished yet.

Recent studies in the United States and Europe indicate that many parents are open to the cryopreservation of pre-pubertal testicular tissue for future FP possibilities. However, current guidelines still classify this tissue collection as experimental and advise its practice only within established research protocols.

Challenges and Strategies in Implementing Pediatric Fertility Preservation Care

As pediatric fertility preservation (FP) continues to evolve, ensuring effective clinical delivery of these services becomes increasingly important. While guidelines for adult FP are well-established, pediatric FP involves additional complexities. Despite longstanding recommendations for discussing FP with families of newly diagnosed pediatric cancer patients, actual implementation remains inconsistent. Surveys indicate that discussions about the impact of cancer treatment on fertility do not always occur, leading to potential regret among patients.

Understanding the Impact of Cancer Treatments on Fertility in Childhood Cancer Survivors

The growing population of childhood cancer survivors in the United States, currently estimated at 380,000, combined with a slight increase in pediatric cancer incidences, highlights the expanding group of patients entering childbearing age. This demographic is expected to grow, with infertility remaining a significant concern due to cancer treatments. In males, radiation and chemotherapy predominantly affect rapidly dividing spermatogonia, leading to a reduction in later-stage germ cells and potential oligospermia or azoospermia. In females, such treatments often trigger apoptosis in primordial follicles, leading to reduced levels of anti-Müllerian hormone (AMH), accelerated use of surviving follicles, and potential ovarian reserve depletion, resulting in premature ovarian failure.

The risk of infertility varies with the patient’s age and gender, generally being lower in younger and female patients. The specific type of cancer therapy also greatly influences infertility risk. Alkylating agents like cyclophosphamide pose the highest risk, and it is suggested to use a cumulative dose score of these agents to predict gonadal injury and infertility risk. Radiation therapy’s impact is significant too, with certain threshold doses to the testes, hypothalamus-pituitary axis, uterus, and ovaries being particularly detrimental.

Given the multifaceted nature of infertility due to cancer treatments, the overall rates are challenging to pinpoint. However, it is estimated that male cancer survivors face an infertility risk approximately 2.5 times higher than their healthy siblings, with the rate nearing 50%.

The Growing Importance of Addressing Fertility in Childhood Cancer Survivors

While addressing fertility issues might not be the immediate priority in managing pediatric cancer cases, the significance of this concern increases as survivors grow older. Studies have shown that a substantial majority, over 75%, of individuals who have survived childhood cancer express a strong desire to have children in their future. Additionally, there is notable regret among parents and adult male survivors who did not consider fertility preservation at the onset of their cancer treatment. This sentiment underscores the importance of integrating fertility considerations into the initial treatment discussions for pediatric cancer patients.

Guidelines for Fertility Preservation in Pediatric Oncology Patients

Current guidelines stress the importance of counseling all pediatric oncology patients about potential infertility, regardless of age, and recommend referring eligible patients for fertility preservation (FP) discussions. These guidelines vary based on gender and pubertal status.

For male children and adolescents with a new cancer diagnosis, the guidelines suggest:

1. Post-pubertal males can have semen collected via masturbation or testicular sperm aspiration for cryopreservation, ideally before starting chemotherapy to avoid genetic damage. Cryopreserved sperm has been successfully used for pregnancies.
2. Hormonal suppression as a means to preserve gonadal tissue is not proven effective and is not recommended.
3. For pre-pubertal males, testicular tissue cryopreservation is currently experimental and should only be pursued within established research protocols.

Regarding female patients, the guidelines note:

1. Post-pubertal females can opt for oocyte cryopreservation, which is now a standard practice. Couples can also consider embryonic cryopreservation, but these procedures should be carried out in specialized centers.
2. Delays in cancer treatment should be minimized as oocyte collection requires ovarian stimulation.
3. Oophoropexy (surgical relocation of the ovaries) is an option for those undergoing pelvic radiation but its success is variable.
4. Ovarian tissue cryopreservation and transplantation, particularly for pre-pubertal females, remain experimental and should only be offered in conjunction with research protocols.

In pediatric cases, it’s crucial that both parents and the patient are involved in the decision-making process, with both consent and assent obtained. For pre-pubertal patients of either gender, gonadal tissue cryopreservation is the primary option, though its future application in fertility treatments is still under investigation.

Navigating Challenges and Ethical Considerations in Pediatric Fertility Preservation

Despite the existence of guidelines, fertility preservation (FP) discussions are often not initiated with pediatric patients. Studies have indicated that factors like the patient’s younger age and female gender are perceived as barriers by pediatric oncologists. A systematic review identified various obstacles faced by healthcare providers in discussing FP, revealing gaps in knowledge about FP options and procedures, discomfort in discussing sexual practices, and concerns about age or sexual maturity appropriateness.

Challenges also arise from patient and parental factors, including a patient’s prognosis, financial constraints, and the added stress of introducing FP into an already difficult situation. Concerns about consent and parental influence in decision-making were also highlighted, along with a noted lack of educational materials on FP.

Ethical issues in pediatric FP, especially for pre-pubertal patients, are multifaceted. They include potential delays in cancer treatment, family understanding of fertility potential, and the distress or discomfort associated with FP procedures. There are also ethical concerns about future outcomes, such as the impact on gonadal function, financial accessibility, the fate of preserved tissue if the patient does not survive, potential reintroduction of malignant cells, and the health of offspring conceived using FP treatments.

Cost remains a significant barrier in FP, with procedures like oocyte or ovarian tissue preservation being expensive and sperm retrieval and storage also incurring substantial costs. Improvements in insurance coverage and support from advocacy organizations are helping to address this issue, but access is not yet universal.

Establishing formalized oncofertility programs has shown to improve the documentation of FP discussions and increase referrals to FP specialists. Although these findings are not exclusively related to pediatric care, structured programs and referral systems are likely beneficial in overcoming barriers and ensuring appropriate care and counseling for young patients.

Exploring Experimental Fertility Preservation Methods for Pre-Pubertal Cancer Patients

In the realm of fertility preservation for pre-pubertal cancer patients, current options remain largely experimental. Despite this, some centers are preserving gonadal tissue with the hope of future scientific breakthroughs. The primary challenge is developing mature sex cells from the stem cells in immature gonadal tissue.

For female patients, ovarian tissue cryopreservation (OTC) and subsequent retransplantation have shown promise. This technique involves grafting thawed tissue into orthotopic sites, offering the advantage of being applicable regardless of pubertal status and not delaying cancer treatment. However, it carries the risk of reintroducing malignant cells in specific cancers. While OTC with retransplantation has led to successful pregnancies in post-pubertal patients, there’s only one reported case of successful pregnancy from retransplanted tissue collected before menarche. This suggests potential for future fertility options in pre-pubertal girls.

Xenotransplantation of cryopreserved ovarian tissue is another emerging method. In a notable instance, mature oocytes were retrieved from grafted tissue of a 6-year-old patient with Wilms’ tumor, transplanted into immunocompromised mice. In vitro maturation (IVM) of primordial follicles from cryopreserved ovarian tissue has seen some success, though rates are lower in pre-pubertal tissue.

For male patients, sperm cryopreservation is an established method for post-pubertal individuals, but pre-pubertal boys do not produce mature sperm. Research on producing mature sperm from pre-pubertal spermatogonial stem cells (SSCs) is ongoing. Animal studies have shown promising results in SSC transplantation and in vitro spermatogenesis, yet translating these techniques to humans remains challenging.

Grafting of cryopreserved immature testicular tissue, another approach, has been successful in animals but has yet to achieve maturation beyond spermatocytes in human tissue. In vitro spermatogenesis from SSCs has been successful in mice, but efforts with human tissue have not yet produced mature sperm.

Despite these techniques being experimental, a survey by the Oncofertility Consortium Global Partners Network revealed that numerous centers globally offer testicular and ovarian tissue cryopreservation to pre-pubertal patients. While OTC shows more immediate promise, significant challenges persist in using cryopreserved testicular tissue for producing mature sperm.

Understanding the Impact of Cancer on Fertility in Patients

Cancer itself is a known risk factor for infertility, impacting fertility through various mechanisms even before treatment begins. Infertility in cancer survivors is often due to damage to the hypothalamic-pituitary-gonadal axis or the reproductive organs.

The hypothalamic-pituitary-gonadal axis, regulated by a feedback loop, can be disrupted by damage to the hypothalamus or pituitary gland from tumors or related therapies. This disruption leads to central hypogonadism. Primary hypogonadism occurs when tumors or treatments harm the ovaries or testicles. The production of key hormones like luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary gland is crucial for normal gonadal function. These hormones stimulate testosterone production and spermatogenesis in males, and hormonal production and fertility in females. Disruptions at any point in this axis can lead to infertility.

In males, testicular tumors producing β-human chorionic gonadotropin (β-hCG) and α-fetoprotein (AFP) can negatively impact sperm production and quality. Studies have shown that men with testicular cancer often have lower sperm concentrations and altered semen parameters compared to those with other types of cancer.

Leukemia and lymphoma have been identified as risk factors for azoospermia before treatment initiation. It was reported that a notable percentage of cancer patients were azoospermic even before starting treatment.

The immune response to cancer can also impair fertility, with certain cancers causing lymphocytic infiltration and elevated pro-inflammatory cytokines. This imbalance can disrupt the blood-testis barrier, leading to germ cell death and reduced sperm production.

Additionally, systemic symptoms of cancer like severe malnutrition and fever can adversely affect reproductive potential. These symptoms can disrupt spermatogenesis and result in changes in sperm quality.

In essence, cancer can affect fertility in various direct and indirect ways, highlighting the need for early and thorough discussions about fertility preservation options in cancer patients.

Analyzing the Impact of Cancer Treatments on Fertility and Reproductive Health

Cancer treatments, though increasingly effective in managing the disease, can adversely affect the reproductive capabilities of survivors. The American Society of Clinical Oncology (ASCO) provides guidelines, including infertility risk calculation tools considering factors like cancer type and treatment regimen.

Gonadotoxicity in treatments can directly damage the gonads or indirectly impact hormonal production via the hypothalamic-pituitary-gonadal axis. This can lead to permanent or temporary fertility issues, with women experiencing premature ovarian failure. In surgery, the focus is on preserving reproductive function where possible. However, certain surgeries can negatively influence fertility and sexual function, like testicular surgery impacting sperm production or surgeries causing erectile or ejaculatory dysfunction.

Chemotherapy’s gonadotoxicity varies based on several factors, including the type and dosage of chemotherapy. Alkylating agents, for instance, are particularly harmful to spermatogenesis and can cause long-term infertility in men and ovarian reserve loss in women. Radiotherapy’s impact on reproductive capabilities depends on factors like radiation dose, treatment location, and the patient’s age. It can cause DNA damage in ovarian follicles, leading to ovarian atrophy, and affect the hypothalamus and pituitary glands, disrupting hormone regulation.

Hormonal therapies, especially in breast cancer treatment, can also impact fertility. Tamoxifen, used in breast cancer, might cause irregular menses but is generally considered reversible. In prostate cancer treatment, hormone therapy can lead to azoospermia.

Recent advancements in immunotherapy have raised concerns about their potential impact on fertility, sexual function, and hormonal balance. For instance, immune checkpoint inhibitors can lead to primary hypogonadism and other sexual dysfunctions. The exact implications of these treatments on fertility and sexuality are still being explored.

Overall, cancer treatments pose significant risks to fertility and reproductive health, necessitating careful consideration and counseling for patients of childbearing age.

Exploring the Interplay Between Psychological Effects and Fertility in Cancer Patients

Cancer diagnosis and treatment can lead to sexual dysfunction, often related to testosterone deficiency. Research indicates that testosterone impacts neurotransmitter release, affecting mood and emotional well-being. Low testosterone levels can decrease neurotransmitter activity, leading to depressive symptoms.

The diagnosis of cancer, particularly in young patients, often brings high levels of psychological distress. This distress can manifest as depression and anxiety, with incidence rates between 13-25% for depression and 15-20% for anxiety in adolescent and young adult (AYA) patients. These psychiatric conditions can lead to hormonal changes, including decreased testosterone and altered semen parameters, potentially affecting fertility.

Conversely, cancer-related testosterone deficiency can contribute to depressive symptoms. This bidirectional relationship between testosterone levels and depression can significantly impact fertility in oncology patients. Moreover, infertility resulting from cancer treatment is known to increase the risk of emotional distress and psychiatric disorders.

Fertility preservation has become increasingly important in cancer care, especially in pediatrics, due to improved survival rates. Organizations like ASCO and ESMO have issued guidelines for fertility preservation, emphasizing the need for early decision-making in collaboration with healthcare professionals. Techniques like conservative surgery or gonadal shielding during radiation can be employed during treatment. Pubertal status is crucial in determining the appropriate fertility preservation method. In post-pubertal patients, gamete cryopreservation is an option, while pre-pubertal patients, lacking mature gametes, might consider other methods. These techniques should ideally be carried out at specialized centers.

Options for Fertility Preservation in Male Pediatric Cancer Patients

In male post-pubertal children, sperm cryopreservation stands as the most viable option for fertility preservation. Typically, spermarche occurs around Tanner Stage 4. Sperm cryopreservation is often recommended for those at least in Tanner Stage 3/4, with sufficient testicular volume and motile sperm. Collection can be through masturbation, or alternatively, via penile vibratory stimulation or electroejaculation for those unable to masturbate. Stored sperm can later be used for intrauterine insemination, in vitro fertilization, or intracytoplasmic sperm injection.

Hormonal suppression as a method to preserve gonadal tissue is mentioned in the literature but is not widely advocated due to unclear success rates.

For pre-pubertal male patients, lacking mature sperm, testicular tissue cryopreservation is a considered option, albeit experimental. This process involves surgically removing immature testicular tissue and cryopreserving it. A study from Karolinska University Hospital on pre-pubertal boys undergoing this procedure reported no long-term risks. As adults, these patients displayed normal testosterone levels but had smaller testicles and altered levels of reproductive hormones. Despite its potential, this technique is still in the developmental stages and requires further advancement to enable maturation of spermatogonial stem cells into viable sperm.

Fertility Preservation Options for Female Pediatric Cancer Patients

In post-pubertal female patients, oocyte cryopreservation is the preferred method for fertility preservation. This process is more complex than sperm cryopreservation and involves ovarian stimulation using GnRH antagonists, typically starting on the second or third day of the menstrual cycle. The process, including transvaginal oocyte retrieval under sedation, spans about 14 days. These preserved oocytes can later be used for in vitro fertilization or intracytoplasmic sperm injection.

For hormone-dependent cancers, such as breast cancer, this method poses risks due to estrogen’s role in cancer growth. Alternative methods like controlled ovarian stimulation with letrozole are being explored for safer options, although their long-term safety is still under investigation.

Another approach is ovarian suppression using gonadotropin-releasing hormone agonist (GnRH-a) therapy during cancer treatment. This experimental method might reduce ovarian toxicity by inhibiting follicular recruitment. However, there are concerns about the flare effect leading to increased sex steroids and potential bleeding, particularly in children with pancytopenia.

For patients needing urgent treatment, ovarian tissue cryopreservation is the most viable option. This involves laparoscopic surgery to remove and cryopreserve ovarian tissue without the need for hormonal stimulation. The tissue can later be thawed and grafted back, potentially restoring endocrine function and fertility. This method is increasingly recognized as a standard care option and is no longer considered experimental.

Oophoropexy, or ovarian tissue transplantation, is another option, typically for patients undergoing pelvic radiation. It involves relocating ovarian tissue away from the radiation field and is performed as a precautionary measure. However, its success can be variable due to radiation scatter and it is still considered experimental.

In summary, various fertility preservation techniques are available for female pediatric cancer patients, with the choice dependent on the patient’s pubertal status, type of cancer, and urgency of treatment. Each method comes with its own set of considerations and potential risks.

Challenges and Considerations in Pediatric Fertility Preservation

Fertility preservation in pediatric patients faces several obstacles, as identified in a study by the Department of Women’s and Children’s Health at the Swedish Karolinska Institutet. These challenges stem from both external and internal factors. Externally, issues arise from the accessibility and organization of healthcare services. The high costs of these treatments, some of which are still experimental, can limit availability or insurance coverage. Internally, barriers are linked to healthcare professionals’ beliefs and values, as well as parents’ perceptions and assumptions.

Parental decision-making rights and assessing the child’s capacity to make decisions are crucial aspects. Patient autonomy is key, yet ethical considerations around consent and assent arise due to the patients’ age. A lack of family understanding about fertility preservation and concerns over delaying cancer treatment can also hinder decision-making. The initial consultation is often fraught with anxiety and a pressing need to start treatment, especially in cancers requiring urgent treatment initiation, complicating these discussions further.

Cultural and religious beliefs regarding the collection methods and fertility preservation techniques must also be considered, as they can influence decisions. Additionally, theoretical risks associated with cryopreserving and transplanting gonadal tissue containing neoplastic cells, the impact on future gonadal function, and the health of future offspring are concerns that need addressing.

Infertility, while not life-threatening, requires elective treatments. Therefore, ensuring minimal risk in fertility preservation techniques is paramount. Techniques like polymerase chain reaction, flow cytometry, and xenotransplantation are being developed to mitigate such risks.

Oncofertility programs are seen as potential solutions to many of these challenges, but formal programs that standardize fertility preservation practices are not yet widely established globally.