Fertility Preservation in Female Pediatric Patients With Cancer: A Clinical and Regulatory Issue.

To date the three analogues (triptorelin, goserelin, leuprolide) are authorized for various therapeutic indications, such as cancer, endometriosis, uterine fibroids, and precocious puberty. Therefore, the prescription for preventing the risk of POF is typically an off-label use, defined as the use of a medicinal product “ for a medical purpose not in accordance with the authorized product information ” ( 109 ). European Union. Study on off-label use of medicinal products in the European Union. Available at: https://ec.europa.eu/health/sites/health/files . Off-label is not regulated at the European level, but specific national measures have been adopted ( 109 , 110 ). In general, this use is not reimbursable excluding selected cases defined by law. For example, the Recommandations Temporaires d’Utilisation (RTU) provide coverage of recognized off-label treatment by France Health Insurance ( 111 ). Moreover, the Italian national health system (NHS) reimburses an off-label use according to Law 648/1996 based on results from at least phase II trials ( 112 ). The inclusion into the 648/1996 list of reimbursable drugs ensures a nationwide access according to criteria for appropriate use and monitoring defined by the AIFA Scientific Committee in the light of clinical evidence. From 2016 this Italian law allows to reimburse GnRHa for the preservation of ovarian function in pre-menopausal women at risk of premature and permanent menopause following chemotherapy treatment ( 29 ). The Italian regulatory authority defined the eligibility criteria, including age (>18 and <43) and lack of adequate alternative options. Thus, currently the use in the post-pubertal age is not approved and falls within the Italian Law 94/1998 ( 113 ), by which physicians can perform off-label prescriptions (not covered by the NHS) but in individual and exceptional cases. This represents to date a limit for the treatment of this population that could be overcome if the eligibility criteria of Law 648/96 will be modified in order to include even pediatric patients. Currently, to the best of our knowledge no other countries gave a nation-wide approval for this systematic off-label use.

In Europe, nearly 80% of children and adolescents with cancer treated on current protocols survive at least 5 years on average ( 1 ). Improved survival rates have increased the number of childhood cancer survivors (CCSs) entering adulthood after treatment for malignancy, which account for 0.1–0.15% of the general population ( 2 ). The high survival rate in children and adolescents is accompanied by a substantial risk of late adverse events (LAEs). Above all, treatment may interfere with physiological growth and development and have an important impact on health status later in life, whilst some late toxicities may cause premature death. Fertility is one of the most important concerns of CCSs ( 3 , 4 ). The occurrence of fertility impairment in female—reduced pregnancy rates and increased risk of early menopause—after pelvic, abdominal, or spinal radiotherapy, total body irradiation, or chemotherapy regimens containing alkylant agents during childhood and adolescence has been widely documented ( 5 – 8 ). Treatments may deplete or accelerate the decline of the non-renewable pool of primordial follicles in the ovary leading to POF and infertility ( 9 , 10 ). Gonadal toxicity is affected by type, doses and length of therapy ( 11 , 12 ), and by age at treatment (females treated at a younger age are less likely to develop POF, probably because of a higher number of primordial follicles at the time of treatment). POF results in a reduced fertile lifespan and associated risk for involuntary childlessness, which can negatively impact the quality of life ( 13 – 15 ), but also accelerates the risk of developing menopause-associated conditions, such as osteoporosis and cardiovascular disease ( 16 ). Therefore, fertility preservation (FP) represents an important issue for oncologists, fertility specialists and patients. Most recent guidelines ( 12 , 17 , 18 ) state FP should be discussed with the parents (or guardians) of adolescents soon after diagnosis and before starting anticancer treatments. In pubertal and postpubertal adolescents, oocyte cryopreservation is one of the available option for FP during gonadotoxic chemotherapy ( 18 ) ( Table 1 ). Oocyte cryopreservation ( 21 ) requires ovarian stimulation with gonadotropin hormone, ultrasound-assisted oocyte collection, and selection and freezing of oocytes ( 22 ). There are many barriers to the adoption of this option into standard of care. First, oocyte cryopreservation should be carried out before starting chemotherapy and requires time ( 17 ) for ovarian stimulation and follicular growing, with consequent delay in the initiation of oncological treatment. This can be a problem especially in pediatric cancers, which often require urgency to start treatment. The random-start controlled ovarian stimulation protocol, providing for a stimulation at any time of the menstrual cycle, can reduce the time needed for cryopreservation, but for patients with very aggressive diseases no delay is allowed ( 23 ). Moreover, this technique is associated with additional challenges as it requires to acquire oocytes through transvaginal approach ( 24 ), a painful procedure to be performed with sedation and with specialized equipment, which is not often available in pediatric hospitals. Not less important is its emotional and psychological impact for most adolescents, despite their sexual maturity. Treatment options for fertility preservation. *Forbidden in Italy (Law 40/2003); **Reimbursed in Italy for oncologic adult patients according to Law 648/96. Ovarian tissue cryopreservation (OTC), although still considered as experimental, is commonly proposed as an alternative to oocyte cryopreservation ( 18 ). Cryopreservation of the ovarian tissue requires a laparoscopic procedure under general anesthesia and the subsequent freezing of the tissue that contains most primordial follicles ( 25 ). Differently from oocyte cryopreservation, OTC can be performed at any time with less delay in starting cancer therapy. Once the patient is disease-free, an autotransplantation can be carried out. Major issues of OTC include ischemic damage to the tissue and the theoretical risk of reintroducing malignant cells, especially. Indeed, transplantation is not in patients with diseases associated with a high risk of ovarian metastases ( 26 , 27 ). Another limitation is represented by the availability of a center with adequate cryoconservation competences and able to perform the most sensitive and updated histological analysis before transplantation to avoid relapses ( 28 ). An alternative, that could represent a more accessible FP option burdened by less discomfort for postpubertal patients, could be the concomitant use of gonadotropin-releasing hormone (GnRH) analogs (triptorelin, goserelin, leuprolide) during the course of chemotherapy ( 18 , 29 , 30 ). This non-invasive and less expensive approach could allow preventing POF in cancer survivors and has been recently integrated in clinical guidelines ( 17 , 18 , 31 – 34 ). In particular, the updated European Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) recommendations state that GnRHa should be used in addition to the other options ( 17 , 35 ). It is noteworthy that in adolescents and young women with malignancies GnRHa are widely used as an alternative to estro-progestinic combinations for menstrual suppression ( 36 – 41 ), in order to reduce the risk of heavy menstrual bleeding associated with hematologic malignancies or myelosuppression induced by chemotherapy. In this setting, despite significant side-effects simulating the physiology of menopause and the risk of loss of bone mineral density with prolonged use (usually > 6 months) ( 42 ), GnRHa are well tolerated and effective option for menses suppression ( 43 , 44 ) and are generally preferred to oral contraceptives for several reasons. Oral contraceptives have some disadvantages such as the daily regimen, in contrast to the monthly administration of GnRHa. Furthermore, the efficacy of oral contraceptives can be reduced by an erratic absorption due to mucositis, diarrhea, and emesis. Moreover, the use of estrogen-based oral contraceptives for menstrual suppression is associated with an increased risk of venous thromboembolism ( 41 , 45 ). However, one of the most important reason for choosing GnRHa is represented by their possible gonadal protective effect ( 41 ).

SB and LG wrote the first draft of the manuscript. FD checked and revised the draft manuscript. All authors contributed to the article and approved the submitted version.

The open access publication fees will be funded within the AIFA pharmacovigilance grant, project ADR-648 “Monitoring of safety and efficacy of drugs prescribed under Law 648/96”.

Ovarian failure following chemotherapy represents an adverse event with an important impact on health and quality of life of survivors. Oocyte and tissue cryopreservation are the main options for fertility preservation. However, these techniques cannot be performed in all patients in all health-care facilities. Pharmacological treatment with GnRHa is a non-invasive and well-tolerated alternative, which can be offered to all subjects if cryopreservation is not feasible due to clinical or logistic issues. Moreover, combining several methods may increase the odds of success of fertility preservation in eligible patients. The available evidence demonstrates a significant advantage for the survivors who received the GnRHa in the long-term maintenance of ovarian function and preservation of fertility. Italy has officially recognized the off-label use of GnRHa in women at risk of premature and permanent menopause following chemotherapy. However, fertility preservation still represents an unmet medical need in adolescents, especially in those who cannot access to other therapeutic options.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.