Fertility preservation healthcare circuit and networks in cancer patients worldwide: what are the issues?

Figures 1 and 2 show the fertility preservation healthcare circuit for female cancer patients commonly used worldwide. Unlike pubertal boys and men for whom sperm banking is an easy option, pubertal girls and young women face more difficulties when they hope to preserve their reproductive health. The female germ cell (only available in limited numbers) needs to be retrieved surgically mainly after hormonal stimulation, and will be at various levels of maturity depending on the length of the menstrual cycle. Currently, oocytes and embryo banking are standard of care for preserving fertility for reproductive-age cancer patients. The age, cancer site, timing and regimen of cancer treatment determine the optimal FP option. Excepting toxicity of treatments, the success of FP depends on the quality of the initial state of reproductive health of women before treatment. Little is known about the risk factors of various populations that should be taken into account.

Table 1 presents experimental levels, advantages, disadvantages and contraindications for FP options. While embryo cryopreservation is the first and most widely used option in the world, ovarian tissue banking is not universally available. Currently, there are relatively few medical centers with international experience in performing ovarian tissue banking: about 100 worldwide and including 23 in France [12]. An overview of Canadian practices [13] reported activities in terms of in vitro fertilization (IVF) across the country. They reported that 100.0% of IVF centres provide embryo cryopreservation, 82.4% provide oocyte freezing, 29.4% provide in vitro maturation services, and only 17.6% provide ovarian tissue preservation. In the U.S.A., the recourse to gestational carriers is an option for women who have undergone hysterectomy or severe damage to the uterus caused by oncology therapies.

Table 2 presents outcomes of FP options in cancer patients around the world. The total number of live births from the fertilization of mature cryopreserved oocytes exceeded 1000 in 2010 [5]. InVitro Maturation (IVM) was performed worldwide for thousands of conceptions leading to healthy babies. The success rate for ovarian tissue transplantation is still low [14, 15]. Rodriguez-Wallberg et al. [16] showed promising results in terms of recovery of fertility in Nordic countries that have performed ovarian tissue transplantation procedures.

Currently, emerging technology is being developed: ovarian follicle culture in vitro, ovarian follicle transplantation, oogonial stem cells and in vitro activation of ovarian follicles. New FP options will continue to be developed.

For these patients in complex situations, health networks are essential to improve coordination of care, and the strengthening of this coordination is a major challenge to improve the performance of the health system. Functional support is required to mobilize all the necessary resources and guarantee an efficient healthcare circuit.

Two major international networks have been created in order to foster scientific exchange between countries and to standardize the FP healthcare circuit for cancer patients. In 2015 the International Network on Cancer, Infertility and Pregnancy (INCIP) incorporated the “Cancer in pregnancy” registry founded in 2005. The INCIP established an international registry on cancer during pregnancy and FP during cancer treatment and promotes research aiming to increase knowledge among healthcare workers and the public. The data collected include oncological, gynecological and obstetric data. All cancer types and treatment modalities are included. This international network seeks to work in close collaboration with existing networks notably the European Society of Gynaecological Oncology (ESGO) Fertility Preservation. The FertiPROTEKT network, founded in 2006, includes 100 centers in Germany, Austria and Switzerland to date. This network will now register their cases in the INCIP network. A German team [17] studied the impact of the creation of the FertiPROTEKT network and showed a significant increase in pregnancies within the first 2 years after breast cancer diagnosis in the period from 2010 to 2012 compared to the period from 2000 to 2002.

In the available literature, the governance of oncofertility is clearly identified in the public health policies of 4 countries: USA, Canada, Brazil and Australia-New Zealand. Table 3 presents networks and strategies of coverage worldwide. The French Society of Oncofertility was created as an association in 2013. The aim was to inform health professionals and the general public about the oncofertility field and to establish best oncofertility practices. In the development process, this association, located in Bondy, should be able to extend its task force to reach national scope. The European Society of Human Reproduction and Embryology (ESHRE) established in early 2017 a Special Interest Group focusing on FP, with the mission to support collaboration between European countries and with relevant professional bodies and societies. Health networks specialized in cancer research sometimes have a fertility preservation axis. In Europe, the ESGO has a FP task force responsible for promoting knowledge among healthcare workers and patients about oncofertility through national and international collaboration among specialist healthcare workers to promote research in order to develop new strategies for FP. In France, the regional network ONCOPACA has developed a regional Cancer and Fertility platform and a regional charter. FP is an objective of the French national Cancer Plan for the period 2014-2019, although there is no structured national network as yet. The Japanese Society for Fertility Preservation and the Korean Society for Fertility Preservation founded respectively in 2012 in Japan and 2013 in Korea, have created national FP networks including the oncofertility field. In low and middle countries, no structured preservation network was identified. In a study conducted in 2015, Mahajan [18] expressed the need for India to structure a multidisciplinary collaborative network to improve awareness of healthcare workers and FP service availability.

National guidelines have been established in the U.S.A. by the American Society of Clinical Oncology (ASCO) [19] and the American Society for Reproductive Medicine (ASRM) [20] in 2013 and by the National Comprehensive Cancer Network (NCCN) in 2014 [21]. In Europe, guidelines have also been published by the ESHRE [22] and by the European Society of Medical Oncology (ESMO) 2013 [23]. There was also the publication of a report in France by the National Cancer Institute (INCa) and the Biomedicine Agency in 2013 [6] and in the U.K. by National Institute for Health and Clinical Excellence (NICE) in 2004. In Australia- New Zealand, an Australasian Oncofertility Consortium Charter was produced in 2015 by the Australasian Oncofertility Consortium. The International Society for Fertility Preservation established recommendations about this topic in June 2012 [24]. All these guidelines recommend universal access to FP facilities for young patients with cancer.

Table 4 presents an evaluation of knowledge, attitudes and practices of healthcare providers in the world. Forman et al. [25] concluded in a nationwide survey in the USA that 86% of oncologists consider it acceptable to sacrifice less than 5% reduction in disease-free survival to preserve fertility outcomes and 36% suggested that women would be willing to sacrifice more than 5%. Lack of time and lack of knowledge are identified as the main barriers to the initiation of FP discussion. Training of healthcare providers remains a challenge to meet the needs of quality of life of the patients. Kohlër et al. [26] showed that gender disparities in access to healthcare are strikingly against women. Table 5 presents an evaluation of healthcare circuits for patients worldwide.

The paucity of nationwide referral networks is a challenge for the activities of international networks. Access to services remains limited, even in developed countries with specific health networks [13, 27] and to the best of our knowledge, no action plan has been published to develop the field of oncofertility in low and middle-income countries.

Financial costs for FP treatments are one of the major challenges thus far. In the U.S.A., in the state of Massachusetts, initial oocyte retrieval without medication costs 6000-12,000 USD and annual storage is around 440 USD [28]. In Canada, oocyte retrieval with intracytoplasmic sperm injection without medication is reported to cost 6000-8150 CAD, embryo cryopreservation ranged from 500 to 1200 CAD and oocyte retrieval and cryopreserved ranged from 2900 to 5400 CAD. The annual maintenance fee for cryopreservation and storage range from 200 to 800 CAD [13]. In 2013, Quebec was the only province in Canada that covered this cost burden. In Germany, cryopreservation of fertile eggs costs about $3400 and annual storage about $280 every year. In India, Mahajan et al. [9] showed in a study of Indian gynecologists that the second most common reason for not discussing the impact of cancer treatment on fertility was the cost of FP techniques (reason expressed by 34.5% of the gynecologists), after lack of available FP services in the city (35.9%). Geue et al. [29] indicated that these annual storage fees could easily become a psychological pressure for couples. In Belgium, the costs for GnRH analogues in not reimbursed. France is one of the few countries that offer women the assurance of financial reimbursement. Globally, financial reimbursement remains a thorny issue and FP imposes significant costs worldwide, restricting care access to women with low financial resources.