Being able to have children could have an important positive effect on the future lives of pediatric cancer survivors. Working at a cancer institute makes us responsible for filling the gaps in our knowledge in this area of patient care.
We describe our activities in a series of young females diagnosed with cancer and evaluated for fertility preservation options. We discuss the developed skills and organization as well as the practical difficulties encountered in managing fertility preservation.
Since September 2012, laparoscopy and cryopreservation of cortical ovarian tissue has been performed in 16 girls (with ovary transposition in 3, and after several cycles of chemotherapy in 5) and egg banking in 4 young women (before chemotherapy in 2 and several years after treatment in 2).
Recommendations on fertility preservation indicate that discussing the problems early on is crucial to future success. It is unthinkable to simply provide information and offer the opportunity to choose a fertility preserving technique without helping and accompanying patients and their families in their decisions and choices on the matter.
Tumori 2016; 102(2): 174 - 177
Article Type: ORIGINAL RESEARCH ARTICLE
AuthorsMonica Terenziani, Cristina Meazza, Maura Massimino, Paola Viganò, Lorenza Gandola, Giorgia Mangili, Francesco Raspagliesi, Davide Biasoni, Marta Podda, Laura Veneroni, Francesca Filippi, Giovanna Riccipetitoni, Edgardo Somigliana
- • Accepted on 29/10/2015
- • Available online on 17/12/2015
- • Published in print on 18/04/2016
This article is available as full text PDF.
Established and experimental methods for preserving fertility have become available in recent years and cancer patients and their families show great interest in this topic (1). It has been reported that patients’ concerns about their future fertility rank second only to questions about mortality (2, 3). Many articles have discussed the barriers encountered in efforts to deal with this issue, and the number of publications on the topic has increased in recent years (4, 5). Some approaches to fertility preservation may involve delaying a patient’s treatment or the need for different professionals to work jointly on a patient’s treatment plan (6).
Working at a cancer institute makes us responsible for filling the gaps in our knowledge in this area of patient care and drawing more attention to the growing importance of fertility preservation. In 2012 our institute started a cooperation scheme and developed a network with 2 fertility preserving departments offering oocyte cryopreservation. One of them was also equipped for processing and banking ovarian tissue.
In this report, we describe our activities for preserving fertility in children and adolescent females, the skills and organization that we have developed, and the practical difficulties encountered in managing fertility preservation.
A fertility professional (a gynecologist) was available once a week to assess inpatients and outpatients for the entire cancer institute. At our unit, the risk of infertility was always discussed with parents and patients (according to their age) when their informed consent was requested and before any treatment was started. Specific counseling with the fertility professional was suggested when the risk of infertility was considered high (i.e., in patients who were candidates for high-dose chemotherapy, pelvic radiotherapy, etc.) or at the parents’ or patients’ request.
Patient’s age and pubertal status
In prepubertal children, the only option was ovarian tissue collection, and this was recommended based on the gonadotoxicity of the treatment. Depending on the girl’s age, the procedure was performed by a pediatric surgeon or a gynecologist using a laparoscopic approach. The ovarian tissue was collected by a biologist from the laboratory and a pathology report confirming the absence of malignant cells detected by histology (7) was also produced. In postpubertal girls, the choice was between oocyte collection (a standard and effective procedure) and ovarian tissue collection (a promising option that is, however, still in the experimental stage(8)). It is worth adding that, in pediatric age, the type of disease cannot be influenced by hormonal stimulation, at least not as far as we currently know.
The question of timing
The usually rapid and symptomatic growth of pediatric malignancies does not allow us to delay the start of treatment for more than 7-10 days. Promptness and efficiency are crucial. This interval generally permits ovarian cortex banking, provided the network is fluent and efficient. Oocyte collection may require longer, even if the recent development of random-start protocols (to allow the immediate start of ovarian hyperstimulation) now allows to reduce the time of collection to less than 2 weeks in most cases (9). For this reason, the procedureis generally done in strict collaboration with the 2 fertility preserving centers belonging to our network. However, if the patient lives far away and referral to these 2 centers causes difficulties, the fertility professional handles the contact between the patient and fertility preserving centers closer to the patient’s home.
General health status
In the case of patients with rapidly growing tumors and symptomatic disease, it is sometimes advisable to start chemotherapy immediately, postponing any fertility preserving procedures until 1 or 2 cycles of chemotherapy have shrunk the tumor and restored the patient to a better general health status. Even if the preferred approach in fertility preservation is to collect materials prior to starting cancer treatment, this cannot always be done in clinical practice. Although we realize that collecting materials after treatment is not optimal (10), the richness of the ovarian reserve in the age group considered may, however, allow this strategy.
The need for concomitant radiotherapy to the pelvic area has to be considered, as well as the need for chemotherapy. In patients prescribed radiotherapy to the pelvis, radiation oncologists estimate the treatment volumes and doses absorbed by the ovaries and uterus. If necessary, they might suggest transposing one or both ovaries outside the radiation field (11), in which case ovarian tissue can be collected as part of the same laparoscopic procedure. The risk of radiotherapy-related damage to the uterus and its consequences for a future pregnancy is also explained to and discussed with the family (12).
Informed consent and costs
Specific informed consent is needed for the laparoscopic procedure, for ovarian tissue harvesting or oocyte collection, and for the related processing and banking. Institutional review board approval (protocol Onco-Fertility) was obtained in January 2011.
In Italy, the costs of all these procedures are covered by the National Health System, except for the pathology report and an annual banking fee. The social worker at our unit can discuss these aspects with a view to partially or totally covering such costs with funds from charities if the patient’s family is unable to do so. We have also begun to test the administration of gonadotropin-releasing hormone agonists prior to commencing chemotherapy in postpubertal girls receiving chemotherapy (13); in such cases, the drugs administered have so far been off label and the expense borne by the patients’ families.
In patients who survived the cancer and who are 17-18 years of age or older, the fertility expert may be called in to assess their risk of premature ovarian failure, any uterine damage caused by radiotherapy, and/or any need for preventive oocyte collection. Given the above-mentioned richness of the ovarian reserve in our age group, one may indeed consider banking oocytes after the end of treatment if the ovarian reserve is not severely compromised. It is relevant to mention here that women in the western world tend to delay seeking pregnancy, and that the ovarian reserve may actually get exhausted in cancer survivors prior to allowing them to fulfill their reproductive wishes.
The multidisciplinary group should consider the favorable aspects but also emotional contraindications related to fertility preservation procedures. The maneuvers can be an implicit and important message of hope provided by physicians about the possibility of healing from cancer. But the proposal of an invasive procedure in addition to those necessary for cancer treatment can be experienced as an excessive burden by some young patients. Clinical experience has also shown the difficulty for some patients to think of a future pregnancy while they are in a phase of life and development in which such projects can be too early. At the same time, the scientific literature reports that the experience of not having been informed about the possibility to preserve fertility is accompanied by feelings of anger and depression (14).
The practical consideration of the high costs of such procedures for the National Health System also raises the question of justifying the choice of not offering them to patients with a poor prognosis. Still different is the problem in countries where the costs are sustained directly by the patient and the family. So the clinical, psychological, ethical and legal sense of a possible prognosis-related cutoff to decide whether or not to offer the preservation of fertility to a patient is something that remains to be defined.
Since September 2012, laparoscopy and cryopreservation of cortical ovarian tissue have been performed in 16 girls with the following diseases: Ewing family tumors (EW) (n = 5); medulloblastoma (n = 4); pineoblastoma (n = 1); Wilms’ tumor (n = 1); non-Hodgkin lymphoma (n = 1); relapsing Hodgkin lymphoma (n = 2); relapsing CNS malignant germ cell tumor (n = 1); soft tissue sarcoma (n = 1). The girls were a median of 13.5 years of age (range 2-16 years). Three girls also underwent ovary transposition at the radiation oncologist’s suggestion. All patients were able to begin their chemotherapy 2-4 days after the laparoscopic procedure. In 5 cases, ovarian tissue was collected after several cycles of chemotherapy had been administered.
Egg banking following ovarian hyperstimulation was performed in 2 patients, a 22-year-old woman with an ependymoma treated with radiotherapy only and a 24-year-old woman with EW. In the second case chemotherapy started with a 23-day delay, which is considered too long by our standards.
After consulting the fertility expert, 4 girls in our series refused any fertility preserving procedures (a 16-year-old girl with relapsing Hodgkin lymphoma and 3 young women including a medulloblastoma patient who already had a child, a patient with medulloblastoma in Turcot syndrome, and a patient with osteosarcoma and a family history suggestive of Li Fraumeni syndrome). In 2 other cases, a proposed fertility preserving procedure was shelved by the pediatric oncologist because of the risk of contamination by malignant cells; the patients were a girl with PNET whose disease subsequently progressed rapidly to the CNS, and a girl with metastatic Wilms’ tumor and peritoneal and pelvic metastases.
Two 18-year-old girls were assessed some years after completing their treatment for medulloblastoma and synovial sarcoma secondary to Hodgkin’s lymphoma, respectively. In both girls oocyte retrieval and cryopreservation were performed.
The iatrogenic sequelae of chemo- and radiotherapy in long-term cancer survivors are an emerging problem in pediatric oncology. Cancer treatments have improved considerably in recent years, giving pediatric cancer patients better chances of survival and consequently making it essential to try and assure these survivors a better future quality of life (2, 3). Being able to have children could have an important positive effect on their future lives, and may be seen as a confirmation for these young people that they are normal and healthy again. The risk of infertility is perceived as a big problem by young women and their parents. On the other hand, it is essential to bear in mind that the provision of fertility preserving options needs to be planned and organized; it is not a simple matter and it may meet with various difficulties. It is important to talk to patients and their families about the cancer diagnosis, the type of treatment needed, the cure rates achieved, the late effects of treatments, and the risk of inherited cancer syndrome in progeny (1); the risk of infertility is one of the issues to discuss.
Recommendations on fertility preservation indicate that discussing the problems early on is crucial to future reproductive success (15-16-17). But this is still only the starting point (18). In our opinion, it is unthinkable to simply provide information and offer the opportunity to choose a fertility preserving technique without accompanying families in their decisions on the matter and guiding them along a properly encoded path. Pediatric oncologists have to decide how much time there is to spare before starting chemotherapy, or whether it is better to delay ovarian tissue or oocyte harvesting until after the patient has had chemotherapy. Radiation oncologists must identify the radiation target volume early on and consult gynecologists on where best to transpose an ovary, if necessary. Then it is up to the fertility professional to choose the best method for a given patient at a given time. For all these aspects to be handled adequately, it is fundamentally important to have a motivated team of specialists with good communication and capable of working together toward the same goal, which is ultimately to give patients the best chances of being cured of their cancer with the least possible iatrogenic sequelae.
Such teams do not develop spontaneously; they have to be nurtured and motivated, primarily by the physicians involved. Multidisciplinary care requires close communication and high levels of up-to-date professional expertise, and it is time-consuming because every single patient needs to be discussed in depth. This area is challenging and rapidly mutable since fertility preservation is a work-in-progress area. However, it has to be faced now (19). We cannot wait for established conclusions since this will take decades from now, in particular in pediatric patients.
- Terenziani, Monica [PubMed] [Google Scholar] 1, * Corresponding Author (firstname.lastname@example.org)
- Meazza, Cristina [PubMed] [Google Scholar] 1
- Massimino, Maura [PubMed] [Google Scholar] 1
- Viganò, Paola [PubMed] [Google Scholar] 2
- Gandola, Lorenza [PubMed] [Google Scholar] 3
- Mangili, Giorgia [PubMed] [Google Scholar] 2
- Raspagliesi, Francesco [PubMed] [Google Scholar] 4
- Biasoni, Davide [PubMed] [Google Scholar] 5
- Podda, Marta [PubMed] [Google Scholar] 1
- Veneroni, Laura [PubMed] [Google Scholar] 1
- Filippi, Francesca [PubMed] [Google Scholar] 6
- Riccipetitoni, Giovanna [PubMed] [Google Scholar] 7
- Somigliana, Edgardo [PubMed] [Google Scholar] 6
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy
Obstetrics and Gynecology Unit, San Raffaele Hospital, Milan - Italy
Pediatric Radiotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori , Milan - Italy
Gynecology Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy
Pediatric Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy
Infertility Unit, Fondazione Ca’ Granda, Ospedale Maggiore Policlinico, Milan - Italy
Pediatric Surgery, Ospedale dei Bambini V. Buzzi, Milan - Italy