Towards enhanced female paediatric oncofertility care and outcome

As childhood cancer survival rates improved to over 80%, emphasis on avoiding long-term side effects including infertility is important, as it has a huge impact on survivors’ quality of life. Chemotherapy and radiation can cause gonadal damage, resulting in a reduced ovarian reserve. For girls at high risk of gonadal damage, it is possible to freeze oocytes or ovarian tissue for future use prior to the cancer treatment. Because freezing oocytes requires delaying therapy and many girls are prepubertal at diagnosis, freezing a complete ovary (ovarian tissue cryopreservation - OTC) is often the only option. From the start of the Princess Máxima Center (in 2015) developing an oncofertility care pathway was a priority. The evaluation of this oncofertility care after the establishment of full national centralization of pediatric oncology (2018) is described in this thesis. Oncofertility care needs a personalized approach because of the wide variation in treatment protocols with their respective risk of gonadal damage. As part of the PEARL (PresErving ovARian function through cryopreservation and informing girLs with cancer about infertility due to gonadotoxic treatment) project, we developed a comprehensive “risk stratification tool” based on the intended treatment, which combined with the 5-step oncofertility plan, accelerates the identification of high-risk patients and increases the likelihood of providing appropriate care. The 5 steps consist of (1) identification of all new patients, (2) gonadal damage risk triage, (3) timely informing all patients before treatment, (4) referral for counseling of all children at high risk of gonadal damage, and (5) offering fertility preservation to these patients. We also developed a questionnaire to evaluate pediatric oncofertility care as part of the PEARL project, which was translated to English and Lithuanian as part of a EU HORIZON twinning (TREL) project. Safety of OTC in children with cancer is being evaluated in the PEARL study, but a knowledge gap remains whether OTC can be safely offered to infants (<1 year of age). Available literature showed that few studies are published on the safety of OTC or other elective laparoscopic abdominal surgery in infants, but our review revealed that morbidity and mortality seem limited. To optimize the identification of groups at risk of gonadal damage, we examined the genetic risk factors for treatment-related gonadal damage using Anti-Müllerian Hormone (AMH), as a proxy for ovarian reserve in adult European pediatric cancer survivors. We discovered two variants of CYP450 enzymes associated with altered AMH values, and while our genome-wide association study (GWAS) yielded interesting hits, these could not be replicated in the American replication cohort. Finally, we explored the risk of micrometastases in ovarian tissue stored for future autotransplantation, as presence of tumor cells in ovarian tissue from pediatric cancer patients is important for future use. This thesis describes the important components of oncofertility care, including feasibility and safety, and the evaluation of this care, as well as the perspectives of fertility preservation including ovarian tissue transplantation.