The Preservation Conversation

Discussions about possible infertility in young patients with cancer should happen early, and often.

Chemotherapy, radiation, and hematopoietic cell transplantation (HCT) are essential treatment options for patients with hematologic malignancies, but these therapies often harm patients’ reproductive health and future fertility. Nevertheless, a survey of nearly 7,000 patients of reproductive age who were diagnosed with cancer found that more than half did not receive counseling about the risk of infertility associated with cancer treatments.1

With recent treatment advances for many cancers, survival rates have improved. Patients are living longer after a cancer diagnosis and conversations about future fertility are now considered an essential part of patient management and survivorship care for young adults, adolescents, and even prepubertal children.

“Ideally, all patients would be informed about the possibility of infertility, even if their current treatment does not put them at great risk,” said Lillian R. Meacham, MD, professor in the department of pediatrics at Emory University School of Medicine and medical director of the Cancer Survivorship Program at Children’s Healthcare of Atlanta. “Several studies have found that, when you ask young adult survivors of cancer what they worry about related to their health, infertility is often one of the top concerns.”

How Does Cancer Affect Fertility?

Infertility after a cancer diagnosis may be related to the disease itself or the therapies used to treat the disease, according to Alison W. Loren, MD, director of blood and marrow transplantation at Penn Medicine in Philadelphia and American Society of Hematology Councillor.

“Some studies have identified that men diagnosed with cancer have lower sperm counts or impaired motility even before being treated,” Dr. Loren said.

Another small study reviewed outcomes for 164 men diagnosed with cancer who elected to cryopreserve sperm at a single institution, testing baseline sperm count and other semen parameters before and after cancer treatment. More than half of patients with leukemia (57%) and 25% of patients with Hodgkin lymphoma had low sperm counts before undergoing chemotherapy or radiation.2 The researchers also observed that less than 5% of patients used their specimens for reproductive purposes.

A larger, more recent study showed that only 37% of samples from men with leukemia and less than 60% of samples from men with non-Hodgkin lymphoma were considered normozoospermic – having normal counts, function, and appearance – after diagnosis, but prior to any gonadotoxic cancer-directed treatment. Compared with samples from fertile sperm donation candidates, samples from men with leukemia had four times lower median total sperm counts.3

In a 2013 study, researchers looked at a possible connection between azoospermia and the risk of developing cancer. Compared with the general population, the 451 men who presented to an andrology clinic and were found to be azoospermic were almost three times as likely to receive a subsequent cancer diagnosis than men in the overall population.4 In addition, infertile men without azoospermia also had a trend toward a higher rate of cancer.

“It is not uncommon for a young man diagnosed with Hodgkin lymphoma to have a lower sperm count than average,” Dr. Loren said. While the relationship is not well understood, she stressed that proper counseling and planning could still help patients retain their fertility.

While less studied, cancer prior to treatment may affect fertility in women too. In addition to direct destruction of oocytes in the ovary form a tumor, maturation and support of the oocytes, as well as normal uterine function could be affected by the presence of a malignancy.

“Several studies have found that, when you ask young adult survivors of cancer what they worry about related to their health, infertility is often one of the top concerns.”

—Lillian R. Meacham, MD

Cancer Treatment and Infertility

In contrast, the effects of certain chemotherapies on future fertility is much better understood, Dr. Meacham said.

Gonadotoxicity can occur when the testes or ovaries are exposed to alkylating agents such as cyclophosphamide, ifosfamide, busulfan, or other high-risk drugs such as platinum-based agents. Radiation to the pelvis, abdomen, or brain, including total body irradiation, can also have a gonadotoxic effect. In addition, any type of bone marrow transplant, even reduced-intensity approaches, can cause infertility, Dr. Meacham said.

This occurs through several mechanisms, Dr. Loren noted.

“In men, sperm are continuously being produced. Those drugs can directly affect growing and dividing cells, leading directly to spermatozoa toxicity,” she explained.

Dr. Loren noted that women, on the other hand, are born with all the oocytes they are ever going to have. As dormant cells, oocytes should theoretically be protected from the adverse effects of chemotherapy. Some of the gonadotoxic mechanisms on female fertility are thought, instead, to be related to damage of the supporting cells that help nourish oocytes.

“Another well-established mechanism relates to growing oocytes that start to die when exposed to gonadotoxic therapies and release signals that stimulate additional oocytes,” Dr. Loren said.

This over-recruitment means more primordial follicles begin growth to replace damaged developing oocytes, making them more susceptible to the effects of chemotherapy than they would be in a resting state.

“One thing is clear: Women who receive chemotherapy are at risk of either permanent loss of their fertility or, if they regain normal menstrual function, they are at risk for early menopause because of a depleted supply of eggs,” Dr. Loren said.

Options for Preserving Fertility

In 2018, the American Society of Clinical Oncology updated its guidelines for fertility preservation in patients with cancer, recommending that health care providers “initiate the discussion on the possibility of infertility with patients with cancer treated during their reproductive years or with parents/guardians of children as early as possible.”5

Mahmoud Salama, MD, PhD, director of the Oncofertility Consortium at Michigan State University, said that, when thinking about fertility options for patients with cancer, clinicians must break them down into categories by sex and age (prepubertal, adolescent, and young adult). Leukemias and lymphomas are among the most common types of cancer diagnosed in children ages 0 to 14, and these conversations will often involve parents or legal guardians, he noted.

For prepubescent boys, the only available option for fertility preservation is testicular tissue cryopreservation. As of 2019, the American Society for Reproductive Medicine (ASRM) still considered this approach to be investigational.6

For adolescent boys or young men, sperm preservation is an option, Dr. Salama said. For boys who have reached the Tanner stage 2 of puberty, sperm banking is the easiest method to preserve fertility. “We always try to preserve sperm before initiation of anti-cancer therapy,” Dr. Salama noted.

While adolescents and men with cancer may not have normal spermatic health, there are several options for preserving their fertility. For example, techniques such as intracytoplasmic sperm injection (ICSI), in which a single sperm is injected directly into the cytoplasm of an oocyte, make it possible for men with poor sperm quality to retain their fertility with proper counseling and planning.

“The fertility preservation process is often a lot harder for girls and young women,” said Stephanie Savelli, MD, director of the Childhood Cancer Survivorship Program at Akron Children’s Hospital in Ohio. “It is more time-consuming and, depending on the diagnosis, there may not be any time to spare.”

For adolescent girls or young women, options are available to cryopreserve oocytes for later in vitro fertilization (IVF) and uterine implantation. If the woman has a partner or sperm donor, the same can be done with embryos.

Prepubescent girls and young women also have the option of ovarian tissue cryopreservation and transplantation. In this procedure, part or all of a patient’s ovary is removed and the tissue containing oocytes is separated from the rest of the ovary, then frozen and stored. The tissue may later be thawed and placed back into the woman’s body.

Ovarian tissue banking was considered an investigational approach for decades, until the ASRM issued a committee opinion in 2019 stating that “ovarian tissue banking is an acceptable fertility-preservation technique and is no longer considered experimental” for patients undergoing gonadotoxic therapy.6 The procedure is indicated for prepubescent girls and those who cannot delay treatment to undergo ovarian stimulation and oocyte retrieval.

However, Dr. Savelli noted that, at this time, ovarian tissue cryopreservation is mostly available at larger academic cancer centers.

Cryopreservation Concerns

Dr. Salama pointed out that patients diagnosed with hematologic malignancies with fertility concerns face several unique challenges, different from the those of patients diagnosed with solid tumor cancers.

“Because leukemia and lymphoma are hematologic diseases, there is a risk that leukemia or lymphoma cells are everywhere in the body, including the gonadal tissue,” Dr. Salama said. “When we cryopreserve ovarian or testicular tissue from a patient, we need to remember that the tissue is contaminated with cancer cells.”

Researchers explored this issue in a small study of 18 women with either chronic myeloid leukemia (CML) or acute lymphocytic leukemia (ALL) published in 2010.7 Samples of patients’ cryopreserved tissue were evaluated for the presence of leukemic cells. Histology did not identify any malignant cells in the ovarian tissue, but quantitative reverse-transcribed polymerase chain reaction (RT-PCR) testing revealed that samples for two of the six women with CML were positive for BCR-ABL. Among the 10 patients with ALL who had available molecular markers, seven tissue samples showed positive leukemic markers. In addition, four mice grafted with the ovarian tissue from patients with ALL developed intraperitoneal leukemic masses. Their findings also revealed that chemotherapy before ovarian cryopreservation does not exclude malignant contamination, “and reimplantation of cryopreserved ovarian tissue from [patients with] ALL and CML puts them at risk of disease recurrence.”

This consideration is very serious, Dr. Salama said, and measures should be taken to test tissue before cryopreservation and again before transplantation.

The second major challenge for patients with hematologic malignancies, particularly those with acute leukemias, is the aggressive nature of the disease.

“Leukemia usually necessitates immediate initiation of anti-cancer therapy,” Dr. Salama said. “The time before initiation is very short, maybe only a few days, and may not provide enough time to address fertility, especially for women.”

The Costs of Fertility Preservation

Many patients with cancer already face financial hardship dealing with the costs related to their diagnosis and treatment. The additional costs of fertility preservation may put these options out of reach.

“Universal insurance coverage for fertility services and reproductive health services does not exist, even in the case of cancer patients and survivors,” Dr. Meacham said.

In a recent publication, Dr. Salama and colleagues estimated that out-of-pocket costs related to fertility preservation ranged from about $1,000 for sperm banking to $12,000 for ovarian tissue cryopreservation.8 However, these costs do not include annual storage fees.

“Sperm banking is relatively inexpensive, but costs do vary by region,” Dr. Meacham said. “Egg harvesting, on the other hand, can cost as much as $10,000.” Oocyte or sperm storage fees at a cryostorage facility can cost about $275 per year, with discounted rates for longer periods of storage. Embryo storage is about $400 per year.9 According to the Alliance for Fertility Preservation, the service and storage fees for oocyte, embryo, or ovarian cryopreservation can cost between $11,000 and $16,000 per year. Options for men range in cost from $650 to $1,400 per year for sperm banking and storage to $10,000 per year for testicular sperm extraction and storage.

“Patients with cancer are planning to keep material frozen for a while,” Dr. Meacham said, noting the potential for high storage costs over the years. “On the back end, there is also the cost of using the material – procedures which currently can cost many thousands of dollars.” Again, she stressed that the costs of these procedures are rarely covered by insurance.

Starting the Conversation

Fertility discussions should be built into the conversations that hematologists have with young patients diagnosed with hematologic malignancies, Dr. Salama said, and the first step is identifying the patient’s risk for future infertility.

“Once they have identified that risk, they have to inform the patient of the risk and help connect them with reproductive medicine specialists or oncofertility teams to preserve fertility before initiation of anti-cancer therapy,” Dr. Salama said.

He also recommended discussing future fertility in situations where the risk may seem minimal.

“In some cases, the initial severity of the disease is not great and the risk of losing fertility may be low,” Dr. Salama said. “After some time, though, the disease may relapse or become refractory, and patients may require more aggressive anti-cancer therapies. In those cases, it is better to have preserved fertility from the beginning.”

Dr. Loren emphasized the importance of having honest discussions with patients about fertility and weighing the risk of infertility with maximizing the chance for a cure.

“In breast cancer literature, data have shown that about one-third of women will change their mind about their treatment plan based on fertility risk,” Dr. Loren said. “Balancing treatment and fertility preservation is not always a clean choice, but these discussions are important.”

A common barrier to having successful conversations about fertility preservation relates to provider knowledge: Hematologists may feel uncomfortable discussing fertility, or ill-prepared.

Infertility and Nonmalignant Blood Disorders

Fertility concerns are not unique to patients with hematologic malignancies; those with nonmalignant hematologic disorders such as sickle cell disease (SCD) or thalassemia may also face these issues.

“We know that with many hematologic abnormalities or any chronic health conditions, we often see a pattern of delayed puberty,” said Lillian R. Meacham, MD, professor in the department of pediatrics at Emory University School of Medicine and medical director of the Cancer Survivorship Program at Children’s Healthcare of Atlanta. “Eventually though, patients achieve puberty and tend to move on.”

However, some will encounter issues with infertility later in life.

For example, as medical advances have improved the quality and duration of life for people with SCD, reproductive issues have come to the forefront.

Infertility in men with SCD may have multiple causes, such as hypogonadism, sperm abnormalities, and erectile dysfunction due to priapism. There is currently no consensus on whether women with SCD are at any increased risk for infertility; lower rate of pregnancies seen in some studies may be due to other factors.1

In addition, as hematopoietic cell transplantation (HCT) remains a mainstay of treatment in SCD, patients who undergo transplant may experience infertility associated with chemotherapeutic agents used prior to the procedure. Questions about the effects of iron overload and use of hydroxyurea on the fertility of patients with SCD also remain.

Patients with thalassemia may also experience infertility due to iron overload in the pituitary gland. Specifically, females with thalassemia may also have premature ovarian aging or primary or secondary amenorrhea due to iron overload.

For patients living with aplastic anemia, effects on fertility will depend on the type of treatment received. Patients requiring HCT may experience premature ovarian failure or decreased levels of hormones.

Because many hematologic disorders are inherited, Dr. Meacham also stressed the importance of genetic counseling in women with these disorders who express interest in becoming pregnant.

“We remind people that they carry the sickle cell gene, for example, and discuss getting their partner tested,” she said. “We also mention things like in vitro fertilization and preimplantation genetic diagnosis.”

Any patient or family who receives a hematologic disorder diagnosis should be counseled about possible effects on future fertility and available fertility preservation options.

Reference

Smith-Whitley K. Reproductive issues in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2014;2014(1):418-424.

“There needs to be connectivity between the hematology team and a reproductive endocrinologist to help patients get information or expedited appointments,” Dr. Loren said. Reproductive endocrinologists specialize in diagnosing and treating endocrine disorders that are either directly or indirectly related to reproduction.

Even if a hematologist is comfortable discussing fertility, though, each conversation differs according to the patients and their unique scenarios, Dr. Savelli said. “I [see] a lot of young men whose first comment is, ‘I didn’t want kids anyway,’” she said. “That is a bit of a reactionary statement, and I try to talk it through with the patient and their parents.”
In cases of adolescents and children, parents and caregivers have a big stake in their child’s future fertility, she added.

Fertility is also part of the survivorship conversation, Dr. Savelli said. She starts seeing patients after two years off therapy and continues to follow patients until age 25. For young men, they discuss sperm analysis to determine whether there are problems with sperm production or motility. “If results are discouraging, I try to tell them that sperm production can recover in many men,” she explained.

In young women, Dr. Savelli recommends anti-Mullerian hormone level testing, which provides a rough estimate of ovarian reserve. In the past, she would recommend that women consider having children earlier in life when they still have more ovarian follicles, but now she can recommend egg harvesting.

Dr. Savelli’s practice works with a fertility group, and she recommends that women have a consultation with the fertility team to determine the currently available options and the options that might be available in the future if they choose not to egg harvest and have difficulty becoming pregnant. “I want to have these conversations early and often,” she said.

The Patient Perspective

The conversation about fertility preservation options often introduces other topics of concern, including the risks of birth defects from anti-cancer therapies or the child’s risk of developing cancer, according to the hematologists who spoke with ASH Clinical News.

“A fair amount of published research has shown no increased risk of birth defects in children born to childhood cancer survivors – men or women,” Dr. Savelli said, acknowledging that some research has shown an increased risk for preterm birth.

As part of her survivorship program, Dr. Savelli refers survivors and their families to a genetic counselor.

“Most of the pediatric cancers we treat have no genetic component,” she said. “We try to put that fear to rest.”

Dr. Savelli added that young patients with cancer and their families also express concern about sexual development and health. She explains to patients and families that certain chemotherapeutic agents can affect a child’s ability to go through puberty on time, but it is uncommon to see pubertal delay.

Regarding sexual health, she approaches the topic the same way any pediatrician would. “When the patient becomes a teenager, I have an initial conversation about the topic – almost always with the parents present,” Dr. Savelli said. “When it is time for an exam, I ask the parents to leave the room. During that time, I talk with the adolescent about sex practices, sexual health, and any concerns they may have regarding sexual health.”

Drs. Loren and Savelli also emphasized the importance of explaining to all patients – adolescents or young adults – that risk for infertility is not the same as birth control.

“If they do not want to get pregnant or get someone pregnant, they need to use contraception,” Dr. Loren said. Patients also should use protection to prevent transmission of infectious diseases, especially those patients who may be immunocompromised.

Building the Team

As fertility becomes a larger part of the survivorship conversation, addressing these needs will require a greater focus on oncofertility. A multidisciplinary team composed of experienced oncologists, reproductive endocrinologists, nurses, patient navigators, and others can work together to help preserve fertility in young patients with cancer. In hospitals where ovarian or testicular tissue preservation is available, this team may also include urologists and surgeons.

For physicians looking for more resources about fertility, Dr. Salama pointed to the Oncofertility Consortium and its website, which allows physicians or patients to search for a clinic or center in their area.

“This idea of a network is very important because some of these sophisticated procedures are not available in each hospital or even each state,” Dr. Salama said. “To provide the best care possible to our patients, we may need to involve many teams, even from different states within the network.” —By Leah Lawrence

References

  1. Patel P, Kohn TP, Cohen J, et al. Evaluation of reported fertility preservation counseling before chemotherapy using the Quality Oncology Practice Initiative Survey. JAMA Netw Open. 2020;3:e2010806.
  2. Chung K, Irani J, Knee G, et al. Sperm cryopreservation for male patients with cancer: an epidemiological analysis at the University of Pennsylvania. Eur J Obstet Gynecol Reprod Biol. 2004;113 Suppl 1:S7-S11.
  3. Auger J, Sermondade N, Eustache F. Semen quality of 4480 young cancer and systemic disease patients: baseline data and clinical considerations. Basic Clin Androl. 2016;26:3.
  4. Eisenberg ML, Betts P, Herder D, et al. Increased risk of cancer among azoospermic men. Fertil Steril. 2013;100:681-685.
  5. Oktay K, Harvey BE, Partridge AH, et al. Fertility preservation in patients with cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2018;36:1994-2001.
  6. Practice Committee of the American Society of Reproductive Medicine. Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertil Steril. 2019;112(6):1022-1033.
  7. Dolmans M-M, Marinescu C, Saussoy P, et al. Reimplantation of cryopreserved ovarian tissue from patients with acute lymphoblastic leukemia is potentially unsafe. Blood. 2010;116(16):2908-2914.
  8. Salama M, Sandler V, Woodruff TK. Managing Reproductive Disorders in Cancer. November 2019. In: Williams Textbook of Endocrinology; Edition: 14 Edition. Chapter: 46. Publisher: Elsevier.
  9. The Alliance for Fertility Preservation. Paying for treatments. Accessed August 5, 2021. https://www.allianceforfertilitypreservation.org/costs/paying-for-treaments.