|Year : 2019 | Volume
| Issue : 1 | Page : 1-4
Overview of Oncofertility
Department of Gynecology and Obstetrics, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
|Date of Submission||19-Feb-2019|
|Date of Web Publication||11-Apr-2019|
Department of Gynaecology and Obstetrics, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Ma D. Overview of Oncofertility. Reprod Dev Med 2019;3:1-4
Prof. Ma, a chief physician, and an academician of the Chinese Academy of Engineering, has devoted himself to clinical medical work for 30 years. Prof. Ma is skilled at the diagnosis and treatment of gynecological oncology and general gynecological diseases and is particularly proficient in gynecological surgery, endoscopy, and robotic surgery. Prof. Ma also made tremendous achievements in the field of prevention and treatment of gynecological tumor, tumor metastasis and translational medicine. Prof. Ma is currently serving as the Chairman of the National Key Disciplines of Obstetrics and Gynecology and National Center for Obstetrics and Gynecology Clinical Medicine Research and Editor-in-Chief of Gynecology and Obstetrics (a national planning textbook for medical students of the 8-year training system) and its English version. As the Chairman of the Society of Obstetrics and Gynecology Professional Committee of Chinese Medical Association, the Executive Director of the China International Exchange and Promotive Association for Medical and Health Care, and the Chairman of the Professional Committee of Health Care of Women and Children, Prof. Ma is prominent and highly regarded in the realm of gynecology/obstetrics and tumor research.
Malignant tumors are the leading life-threatening causes, and the rising cancer rates among young patients has drawn increasing attention. According to the statistics, in the United States, there are approximately 879,000 newly diagnosed female cancer patients, while in China approximately 2,400,000 patients are affected by malignant tumors each year, accounting for ~ 20% of cases with malignant tumors worldwide. The number of patients with cancer in the past 10 years has reached 24,000,000. With improvements in cancer screening and health care, more patients with cancer have been diagnosed in the early stage, and the number of young patients, children and teenagers diagnosed with cancer, has also increased. Twenty-five percent of patients with breast cancer are younger than 40 years, and the new cases aged <40 years reach approximately 12,500 annually. The second peak occurs at the age of 15–30 years and 45–55 years. The youngest reported patient with cervical cancer in the world was 13 years old. Meanwhile, with the development of medicine and bioscience, the prognosis of most patients with cancer has greatly improved, and survival rate among young patients with cancer has dramatically increased; the mortality rate among those younger than 20 years has decreased from 0.065% in 1970 to 0.023% in 2015; and the 5-year survival rate has increased from 58% in the 1970s to 83% in 2007–2013. The increase in the incidence rate and decrease in the mortality rate lead to cumulative increases in the absolute number of young patients with malignant tumors after treatment. How to maintain health and guarantee a good quality of life for young cancer survivors during treatment period poses a new challenge.
Traditional tumor treatments such as surgery, chemotherapy, and radiotherapy can severely impair the organs and functional performance of patients. They can cause irreversible fertility and the endocrine function impairment of young patients and severely affect their quality of life; thus, patients suffer from both tumors and toxic effects caused by treatments, such as severe damage to their hematopoietic, hepatic, renal, and sexual fertility (or even permanent loss of fertility) functions, as well as psychological sufferings, such as depression and anxiety. Today, China is shifting from traditional biomedical model to physiological, psychological, and social medical models. Future fertility and effective maintenance of the ovarian function of young patients with cancer have recently become popular research topics. Reproductive health is an important issue related to national interest, livelihood, and population quality, and fertility is the top priority in relation to the quality of life of cancer patients. Reproductive health is not only in the interest of maintenance of family happiness and social harmony but is also conducive to promoting sustainable development of medical and health services as a whole.
Meanwhile, reproductive medicine advancements have greatly improved modern medicine. The first generation of oral contraceptives in the 20th century introduced a rational contraception method. At the end of the 20th century, the first in vitro fertilization (IVF) baby and cloned animal were born based on investigations on the mechanism of gametogenesis, maturation, and fertilization. The Nobel Prize in Physiology or Medicine was therefore awarded to Robert Edwards – groundbreaker in human assisted reproductive technology, recognizing the remarkable contributions to humans, and then good news keep coming in, such as the first cryopreservation of a sperm, recovery of a freezing embryo, cryopreservation of an egg, injection of a single sperm to the oocyte plasma, and pretransplant diagnosis, which dramatically boosting the morale and commitments to the researchers in this field.
The rapid development of assisted reproductive technology makes it possible for fertility preservation among patients with cancer. The primary basis for fertility preservation depends on the progress of the cryopreservation technology in reproductive medicine laboratories. Programmed embryo cryopreservation is a standard regimen for fertility preservation of patients with cancer at reproductive age. Other technologies, such as gamete cryopreservation and embryonic vitrification-cryopreservation, have also attracted increasing attentions. However, for patients in critical condition, juvenile patients, and patients sensitive to hormones, gamete or embryo cryopreservation may not be feasible. Thus, an in-depth exploration is needed (i.e. whether cryopreservation and reimplantation of ovarian or testicular tissues, cryopreservation of immature follicles, or in vitro maturation can be feasible to regain fertility for patients with cancer). Comprehensive evaluation of the possibility and risk of fertility preservation before treatment; selection of the most appropriate method during treatment among young patients with malignant tumors; selection of a personalized tumor therapeutic strategy that protects patients' reproductive function (including tailor-made surgery and postoperative chemoradiotherapy protocol); and selection of the best timing to apply corresponding assisted reproductive strategy after treatment; They all involve the establishment of a systematic research system and treatment philosophy. They also break new ground in reproductive medicine and biomedicine research, and give birth to the new concept of oncofertility.
| Origin of Oncofertility and Current Status Worldwide|| |
Oncofertility is a new discipline involving oncology and genesiology, first proposed by Prof. Teresa K. Woodruff (a famous professor in Obstetrics and Gynecology), who published Oncofertility Fertility Preservation for Cancer Survivors (the first book on oncofertility) in 2006. Thereafter, the oncofertility special fund was supported by the National Institutes of Health ($21,100,000). Later, an Oncofertility Consortium was founded, aiming to achieve preservation and recovery of fertility for patients with malignant tumors receiving antitumor treatments. The Oncofertility Consortium is also responsible for the successful and safe translation of basic science research from the bench to clinical application at the bedside through organizing and coordinating clinical physicians, scientists, sociologists, ethicists, and anthropologists. Meanwhile, oncofertility was supported by the American Society of Clinical Oncology (ASCO) and the American Society for Reproductive Medicine (ASRM). The ASCO and ASRM have recently issued specific guidelines for physicians regarding the influences of antitumor treatment on fertility, treatment strategies that are helpful for fertility preservation, relevant medical support, personalized therapeutics and recommendations of reproductive specialists.
In China, approximately 24,000,000 patients have been affected with cancer in the past 10 years, and young patients account for a considerable proportion. Scientists in China have made great improvements in the surgical procedure and chemoradiotherapy protocol suggested by foreign guidelines to achieve fertility preservation. In the 1970s, a major breakthrough in the treatment for trophoblastic tumors was achieved in China, which improved the prognosis and preserved the fertility of most young patients. In the past 10 years, our team (Prof. Ding Ma, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology) established a research system: Protection for Fertility and Female Endocrine Function of Patients with Gynecologic Cancer, especially focusing on patients with early-stage cervical carcinoma receiving neoadjuvant chemotherapy with extended cervical conization instead of radical trachelectomy suggested in the traditional guidelines for cervical cancer. To date, a total of 12 patients with successful fertilization have had healthy children. The results were published in the European Journal of Cancer in 2012, receiving worldwide attention. Meanwhile, we have achieved significant advances in using light toxic gonads instead of heavy counterparts to treat trophoblastic tumors and nonepithelial ovarian tumors with multiple clinical trials. The results of two clinical trials were presented in the conference of the Society of Gynecologic Oncology in 2018, which was highly recognized by international colleagues. On the one hand, Chinese scientists laid a good foundation in protecting the fertility function of young patients with cancer; on the other hand, reproductive science therein has been developing at a rapid pace, proposing the concept of protecting the fertility and endocrine function of patients with cancer. However, we still have a long way to go to make substantive cooperation between oncology and reproductive medicine possible, and build up a systematic framework of oncofertility, which is a vacuum in research. Oncofertility is a systematic engineering and its involving problems of each discipline needs comprehensive exploration and discussion. Chinese scientists should jump at the opportunity window of oncofertility and endeavor to catch up with international pioneers to play a leading role in the field.
In the aspect of fertility preservation for patients with cancer, the research focus is the development of various gonadal protectants. The common gonadal protectants are gonadotropin-releasing hormone agonists (GnRH-a), antioxidants, and molecular targeting reagents. As a traditional ovarian protectant, GnRH-a is controversial. According to our previous study, GnRH-a was only applicable in the gonad protection against a few drugs with light gonad toxicity. We revealed the mechanism of specific drug protective effects for the first time, which could be laboratory evidence for the appropriate application of GnRH-a. There are many types of antioxidants, and most of the related studies mainly focused on in vitro cell culture. Thus, validating data and data on molecular biological mechanisms are lacking in animals. Moreover, most of them did not investigate the influence on tumor therapeutic effects, which needs further optimization and design to clarify the physiological and side effects. Molecular targeting reagents have also become a popular research topic in oncofertility recently, but it is still in the infancy which calls for in-depth exploration by professionals. With the rapid progress of medicine and biology to date, the prognosis of most patients has significantly improved. For young cancer survivors, how to maintain health and guarantee a good quality of life becomes a challenge.
Recently, remarkable achievements have been made in tumor and reproductive research in China. Mature and applicable fertility preservation methods in clinics include sperm, mature oocyte, and embryo cryopreservation. Sperm cryopreservation is a mature and effective fertility preservation method, but is infeasible for men before sexual maturity. Mature oocyte cryopreservation is applicable for women in the sexual maturity period, but needs a certain treatment cycle. A legal spouse is the prerequisite for embryo cryopreservation. The abovementioned indications suggest that fertility preservation of adolescents is still a challenge in the clinical setting.
In general, fertility preservation is applicable for women with malignant reproductive system tumors, focusing on innovation and improvement for surgical techniques. Studies on fertility preservation mainly focus on treatments that can impair the reproductive or endocrine function (i.e. chemoradiotherapy), as well as on gonad protection. On the one hand, essential questions can be drawn from clinical practice on the basis of the mechanisms of surgery, chemotherapy, radiation damage and germ cell damage, and on the other hand, a nationwide research framework guiding in-depth discussion on oncofertility should be built through cooperation between oncologists and reproductive scientists. Currently, clinical research and some basic studies on oncology and genesiology are at the forefront worldwide.
| Important Development Direction for Oncofertility in the Future|| |
Exploration of reproductive function protection before tumor treatment
The fertility preservation method before malignant tumor treatment arises from the development of the cryopreservation technique. Semen, testicular, and epididymis cryopreservation is the main strategy for men and embryo, oocyte, and ovarian cryopreservation for women. The molecular basis of cryopreservation protection for reproductive cells is more important.
Embryo cryopreservation involves freezing of an embryo using special protective agents and cooling measures to stop or minimize its metabolism in liquid nitrogen at −196°C, without losing the capacity of recovering the metabolic function after being thawed – a biotechnology that preserves an embryo for a long time. Embryo cryopreservation is a conventional fertility preservation method in the clinical setting, with a pregnancy rate of 40% after thawing and transplantation. However, this method needs stimulation in the ovary to collect mature eggs and cryopreservation after fertilization, which is feasible for married women. Some patients with cancer have negative responses to conventional IVF stimulation, leading to reduction in egg number or quantity. Moreover, the serum estrogen level is elevated at the time of controlled ovarian hyperstimulation. Therefore, conventional controlled ovarian hyperstimulation should be avoided among hormone-dependent patients with breast cancer or endometrial carcinoma. Instead, regimens with less estrogen exposure are preferred, such as microstimulation or egg retrieval during the natural cycle. Problems such as personalized embryo cryopreservation regimens based on individual characteristics and physicochemical properties of germ cells under super-cryopreservation and recovery of thawed germ cells need to be further explored.
Oocyte cryopreservation can avoid ethical issues related to embryo cryopreservation. However, it has its limitations, owing to the fact that oocyte is too large cell volume and water content is too high and the spindle body is easily destroyed by ice crystal during freezing or recovery. Cryoprotectants can affect the cytoskeleton, increase the incidence rate of aneuploid development in the oocytes, and cause induration of the zona pellucida and difficulty in fertilization after cryopreservation. These are the reasons for pregnancy rate below 10% after oocyte recovery, limiting wider application of oocyte cryopreservation in the clinical setting, which is a challenge to be overcome in the future. Ovarian tissue cryopreservation is applicable for prepubertal patients or patients with cancer need immediate treatment without enough time for ovulation induction. The technology includes ovarian cortex (tissue mass) freezing, entire-ovary cryopreservation (with vascular pedicle), and isolated follicular cryopreservation (immature oocytes), which are all in the clinical trial stage. Transplantation of ovarian tissues after cryopreservation is based on organ transplantation. If successfully implemented, it can not only solve reproductive problems but also maintain ovarian function and keep aging at bay, which can also be a research focus in the future.
Improvement of clinical diagnosis and treatment to protect reproductive function during tumor treatment
Previous treatments for patients with malignant cancer target at killing the tumor while fail to effectively protect patients' ignoring effective protection of the patients' organs or even causing severe damages. Analysis of the molecular basis of metastasis, recurrence of malignant tumors and effective preoperative treatments (e.g. neoadjuvant chemotherapy) can help keep the injury at the lowest level and preserve patients' fertility as much as possible. For example, patients with cervical cancer receive neoadjuvant chemotherapy with extended cervical conization to maintain uterine function and fertility. Patients with epithelial ovarian cancer at Stage I undergo fertility preservation surgery. Patients with precancerous endometrial carcinoma receive progesterone therapy and breast-conserving surgery. For patients receiving radiotherapy, a dose–effect role of radiotherapy can be found via molecular research on radiation damage to cells owing to the impairment of ovarian function caused by direct radiation and scattering damage. Meanwhile, shielded protection should be considered to minimize the influence on ovarian function. During chemotherapy, GnRH-a treatment inhibits the ovarian function by shielding dormant ovaries from damage of chemotherapy. Relevant molecular basic research on reproductive endocrine will be an important breakthrough for therapeutics. Furthermore, during bone marrow transplantation in hematopoietic diseases, research of the physicochemical properties of injuries on reproductive endocrine cells caused by hyperdose chemotherapy and its corresponding protective measures remains an uphill battle in this area.
While chemoradiotherapy is critical during tumor treatment, it also severely impairs reproductive function. Malignant tumor cells and normal reproductive endocrine cells are both classified into cells with rapid proliferation and differentiation. Killing tumor cells and effectively protecting normal reproductive endocrine cells simultaneously through differentiating them at molecular level; developing targeted chemoradiotherapy protocol; effectively protecting reproductive endocrine cells through molecular targeting and immunotherapy, all of which are important issues need to be explored in the future.
Safety evaluation and regimen-making for reproductive function recovery after tumor treatment
First, the damage to reproductive endocrine cells during tumor treatment should be evaluated, such as premature ovarian failure and ovarian molecular reserve, and to establish an accurate laboratory evaluation method brooks no delay. The important issue in this stage is how to use residual reproductive endocrine cells to maximize the maintenance of the normal reproductive endocrine function. For patients who undergo fertility-sparing surgery, appropriate timing of assisted reproduction should be weighed against tumor recurrence. For example, immature follicles are obtained from ovarian tissues, cultured in vitro, and used for IVF. The corresponding molecular mechanisms of germ cell recovery and functional status are important research directions. Moreover, allotransplantation of the ovary is an important method to recover the reproductive endocrine function of patients with cancer. The risk of increased recurrence of hormone-dependent tumors and safety evaluation still need further exploration.
Since the 1990s, remarkable advancements have already been noticed in life sciences. The first life science revolution founded and developed molecular biology, laying the foundation of microbiological science. The following second life science revolution developed genomics and created the opportunity to explore life sciences further. The third life science revolution considers cross-disciplines the core, allowing effective collaboration among scientists in tumor, reproductive, material, biology, and genetic research. Tumor therapies, including confined surgery, targeted chemotherapy, precise radiotherapy, and assisted reproductive fertility preservation techniques, are considered the core to propose major scientific issues based on the clinical practice of oncofertility and investigate and establish the system of oncofertility via a powerful combination of tumor and reproductive research in China systematically. Oncofertility will definitely not be a mere medical term, but holds promise to treat young patients in the future, and even transform life sciences.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.