Infertility: An obstacle to cancer survivors?
Fertility preservation options for patients with cancer
Cancer is neither an uncommon or rare word for us anymore. Incidences of cancer have an increasing trend worldwide causing a global burden. By today more than a 100 types of cancers have been identified. Aggressive chemotherapy/radiotherapy and bone marrow transplantation can cure most patients affected by cancers requiring such treatment, if detect and treated at the early stages. However, ovaries and testis (gonads), where eggs and sperms are produced, are very sensitive to these cytotoxic drugs, which are classified as having a high risk for gonadal malfunctions. Chemotherapy and radiotherapy can impair gonadal function, rendering patients infertile in many cases. Nevertheless, there are several options, such as freezing egg, embryo or sperm and ovary tissue cryopreservation, currently available mainly in USA and Europe, to preserve fertility in cancer patients. It gives them the opportunity to become parents when they overcome their cancer.
Cancer is the leading cause of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer related deaths (22% of all NonCommunicabl e Disease deaths) in 2012 and it is expected that annually cancer cases will rise to 22 million within the next two decades (WHO). There are many types of cancers that we are aware of and the incidence is increasing day by day. According to the WHO and WCRF, the five most common sites of cancer diagnosed among women are breasts (25.2%), colorectum, lung, cervix, and stomach while among men, these were lung (16.7%), prostate, colorectum, stomach, and liver in 2012. According to the National Cancer Control Program (NCCP, 2009), the leading cancer site in adult females is the breast whereas it is lip, oral cavity and pharynx in adult males in Sri Lanka. Leukemia is the most common cancer among children under 14–years–old in Sri Lanka. Bad food habits, unhealthy life styles, smoking, alcohol, pollution, pathogens and genetic background are some of the causes for cancers. Yet, advances in cancer therapy have improved the long-term survival of cancer patients.
Intense chemotherapy/radiotherapy and bone marrow transplantation (BMT) can cure most of the patients affected by cancers requiring such treatment, if detected and treated at the early stages. The cancer death rate has dropped by 23% since 1991, translating to more than 1.7 million deaths averted through 2012 in USA (CA: A Cancer Journal for Clinicians, 2016). There are a few ways to treat cancer, such as surgery, chemotherapy, radiation therapy, target therapy and immunotherapy while some of these still under experimental conditions. However, both radiotherapy and chemotherapy, especially the alkylating agents, deplete the ovarian reserve in females and damage spermatogenic stem cells (SSC, cells that are responsible for both the continual production of sperm and regeneration following injury) in males, leading to temporary or permanent gonadal failure.
In females, intensive chemotherapy and/ or pelvic irradiationcan decrease the ovarian reserves and results in a greater risk of Premature Ovarian Failure (POF). It is estimated that more than one–third of young women exposed to cancer therapy develop POF. Moreover, chemotherapy induces amenorrhea (The absence of menstrual periods) and the frequency of chemotherapy–induced amenorrhea differs according to the patients age, and the chemotherapy regimen administered. Women undergoing gonadotoxic treatment may suffer a longterm effect on reproductive performance causing female infertility.
Cancer therapy can induce infertility in males by damaging glands that produce sperm or seminal fluid, damaging endocrine-related organs releasing hormones that stimulate puberty and control fertility or by changing the parts of the brain, which control the endocrine system. Concerns affecting fertility may include direct damage to sperm or SSC and low or no ability to produce sperm or seminal fluid. There is continuous production and development of sperm in the seminiferous tubules, located within the testes, making them a key target for chemotherapy. Generally, no sperm production occurs before the puberty, but germ cells are still present and repeatedly divide, consequently making them a target of chemotherapy as well. Germ cells and sperms can also be damaged by radiation, even in low doses. Recovery of spermatogenesis depends on the drugs used and the cumulative dose given.
Advances in cancer therapies have improved the long-term survival of cancer patients. Cryopreservation of gametes or tissues prior to chemotherapy and/or radiation would be an alternative method to preserve fertility. Cryopreservation is a process where cells or tissues are preserved by cooling them to sub-zero temperatures through controlled (slow/rapid freezing) or uncontrolled (vitrification) mechanisms and storing them in liquid nitrogen at 196oC. Several options are currently available for female cancer patients to preserve fertility such as cryopreservation (freezing in simple words) of immature or mature oocytes (eggs), embryos or ovarian tissues. For male patients, the general practice is to freeze ejaculated sperm (sperm banking) and other options are to preserve epididymal sperm or testicular tissues (experimental). Although, these techniques are mainly used as an infertility treatment method in ART (Assisted Reproductive Technologies), it is hardly used for fertility preservation in cancer patients. Preserving gametes or gonadal tissues gives patients a greater chance to become parents when they overcome their disease.
It is a simple and well established strategy to preserve female fertility, as it does not require surgery. The first birth after human oocyte cryopreservation was recorded in 1986. It was started as an ART method to treat infertility. Cryopreserved oocyte is thawed (warmed) and the performance of IVF (In Vitro Fertilization; the egg is allowed to be fertilized by a sperm outside the female body) or ICSI (Intra Cytoplasmic Sperm Injection; a single sperm is injected directly into an egg) in a laboratory. If the oocyte is immature, in vitro maturation is performed before fertilization. The fertilized egg (zygote) is cultured for 2-6 days in an incubator. Then the embryo is implanted in the woman's womb, with the intention of establishing a successful pregnancy. The clinical pregnancy rate per transfer ranged from 36%-61% for mature oocytes (ASRM; Mature oocyte cryopreservation: a guideline, 2013).However, data regarding pregnancy rates after using cryopreserved oocytes in cancer patients is limited. The reproductive potential of oocytes canbe retained for years after cryopreservation. This method can be used by the married women and by unmarried women too, if they are willing to do so.
Generally, it is considered the best option for women having a male partner. Embryo cryopreservation has been the primary modality for fertility preservation and has been available since the 1980s. A InVitro fertilized egg is cultured in an incubator until the embryo stage. Then the embryo is cryopreserved and stored in liquid nitrogen until the woman is ready for implantation. Data on pregnancy and live birth rates in cancer patients after frozen embryo transfers is limited. However, the delivery rate per embryo transfer using frozen–thawed embryos was 31.8% for women less than 35 years of age (reported by SART, 2002). Embryo freezing among partners who are not married is neither ethical nor legal. Married women have all the options but young girls and unmarried woman will have fewer choices.
Two established methods, egg and embryo freezing cannot be applied to prepubertal girls, as these methods require prior ovulation stimulation and subsequent egg retrieval. Therefore, cryopreservation of ovarian tissue might be the only option available for prepubertal girls. For women who cannot delay the start of chemotherapy and for young cancer patients who have recently been exposed to chemotherapy treatment, ovarian tissue cryopreservation might be the only option to preserve fertility, because it mainly preserves primordial follicles.Surgical removal of ovarian tissue causes no delay in cancer treatment initiation and yields an abundance of primordial follicles.
The cryopreservation of ovarian tissues to preserve fertility for patients with cancer has been investigated for decades. To date, the birth of more than 60 babies around the world from the transplantation of cryopreserved ovarian tissue has demonstrated the clinical success of this method (Donnez and Dolmans, 2015). The method involves removing pieces of cortical ovarian tissues before chemotherapy/radiotherapy and reimplanting into an anorthotopic site (on the remaining ovary or close to it or in the uterine environment) or heterotopic site (outside the peritoneal cavity). Natural pregnancy may be accomplished through orthotopic tissue transplantation if the fallopian tubes remain intact. However, it is of paramount importance to analyze the risk of transferring malignant cells with transplanted frozen-thawed ovarian tissues. Ovary tissue cryopreservation will benefit any patient undergoing treatment likely to impair future fertility, the indications being pelvic, extrapelvic, and/or systemic malignant diseases as well as non-cancerous POF.
It is the most simple and established method to preserve male fertility. Usually fresh semen is collected by either masturbation, electro ejaculation or a surgical method (MESA – micro epididymal sperm aspiration or TESE – testicular sperm extraction) and analyzed for quality parameters. Then sperms are cryopreserved in a storage device, generally straws, and stored in liq- uid nitrogen. Later it can be used for artificial insemination (if the sample is enough), IVF or ICSI. Cryopreserved sperms will remain viable for an indefinite amount of time when properly stored. However, a baby has been conceived with frozen sperms after 21 years (BBC news, 2004). A boy preserved his sperms after he developed testicular cancer in 1979 at the age of 17 and later when he got married, two embryos resulting from ICSI were implanted in his wife’s womb in 2001. The technique was developed in 1992, 13 years after the sperm was originally stored. About 15% of men will use their cryopreserved semen because of persistent azoospermia after cancer treatment (Dohle, 2010). The success rate of ARTprocedures with preserved sperms from former cancer patients ranges from 33% to 56% (van Casteren et al.,2008).
It is an emerging fertility preservation technique, still under experimental conditions. It is the only option for prepubertal boys but post-pubertal boys and men can .
also use it. The method involves surgically removing of testicular tissue pieces and cryopreserving them using a propermedium containing cryoprotectants and storing them in liquid nitrogen at 196 °C. In post-pubertal boys and men, thawed tissues are subsequently transplanted as a testicular cell suspension into the seminiferous tubulesor intratesticular grafting tissue. Similar to the ovarian tissues in women, it is important to analyze the risk of reseeding microscopic malignant cells with transplanted frozen-thawed testicular tissue.
It is now well-established in some countries that all patients should receive information about the fertility risks associated with their cancer treatment and the fertility preservation options available. In 2004, the Japan Society of Clinical Oncology, the Japan Society of Obstetrics and Gynecology, and the Japanese Urological Association suggested that oncologists and gynecologists should provide a thorough fertility preservation explanation to breast cancer patients before the start of systemic and radiation therapy (Shien et al.,2014). Clinical practice guideline on fertility preservation has been published by the American Society of Clinical Oncology (ASCO) and European Societyfor Medical Oncology (ESMO).Primary clinical questions the ASCO guidelines address are; Are patients with cancer interested in interventions to preserve fertility? What is the quality of evidence supporting current and forthcoming options for preservation of fertility in males and females? What is the role of the oncologist in advising patients about fertility preservation options? Special considerations addressing the fertility needs of children with cancer are also addressed in this guideline update.Following are the key recommendations published in the recent ASCO clinical practice guideline, 2013. Discuss fertility preservation with all patients of reproductive age (and with parents or guardians of children and adolescents) if infertility is a potential risk of therapy. Refer patients who express an interest in fertility preservation (and patients who are ambivalent) to reproductive specialists. Address fertility preservation as early as possible, before treatment starts. Document fertility preservation discussions in the medical record. Answer basic questions about whether fertility preservation may have an impact on successful cancer treatment. Refer patients to psychosocial providers if they experience distress about potential infertility. Encourage patients to participate in registries and clinical studies. To the best of my knowledge, egg, embryo and sperm freezing are currently practised as an infertility treatment in Sri Lanka but not as a fertility preservation method for cancer patients. A lack of information is the most common reason for failing to practice these methods. Fertility preservation will have a social, economic, ethical and psychological impact on society. Nevertheless, it is time to bring oncologists, gynecologists, urologists, radiologists, pediatricians, surgeons and psychologists to one table to discuss and share knowledge and bring about the mind set to advise young cancer patients on fertility issues. The results would help to build a fertility preservation guidelines to assist healthcare professionals to get a thorough up-to-date knowledge regarding fertility preservation and inform and advise their patients before the start of systemic and radiation therapy. It will not be impossible for us to accomplish this challenge as we have very talented physicians in our country. It will bring hope to young cancer patients who wish to become parents after surviving the battle.
Donnez J and Dolmans MM. Ovarian cortex transplantation: 60 reported live births bring the success and worldwide expansion of the technique towards routine clinical practice. J Assist Reprod Genet 2015; 32:1167– 1170
Dohle GR. Male infertility in cancer patients: Review of the literature. International Journal of Urology 2010; 17(4): 327–331.
vanCasteren NJ, van Santbrink EJ, van Inzen W, Romijn JC, Dohle GR. Use rate and assisted reproduction technologies outcome of cryopreserved semen from 629 cancer patients. Fertil.Steril.2008; 90:2245–50.
Shien T, Nakatsuka M, Doihara H. Fertility preservation in breast cancer patients. Breast Cancer 2014; 21:651–655