Addressing Fertility Issues in Cancer Patients
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For some newly diagnosed cancer patients, whether they will be able to have children after treatment is the furthest question from their minds—until the risks of therapy bring it front-and-center.
In recent years, improvements in treatment and survival expectations have increased the need for cancer patients to make informed decisions about addressing their risk of infertility following therapy.
“Back when the goal was to just have patients survive the disease, worries about whether they were going to be fertile definitely seemed to take a backseat,” said Dennis Hughes, M.D., Ph.D., an associate professor in the Division of Pediatrics at The University of Texas MD Anderson Cancer. “As we’ve gotten better and better at curing people, we’ve had to think more about what the rest of their lives will look like, and this includes their ability to have children.”
Assessing infertility risk
A patient’s risk of infertility depends on the specific treatment the patient will receive. Among chemotherapy drugs, for example, antimetabolites such as methotrexate carry a low risk of infertility, whereas alkylating agents such as cyclophosphamide carry a high risk. Radiation therapy is known to have a high risk of infertility, but methods such as radiation shielding and transposition—using surgery to temporarily move the ovaries out of the intended radiation field—are used to mitigate that risk. Cancer surgery, unless it alters the reproductive organs, generally has a low risk of infertility.
The known risks of various therapies, and how those risks are handled, continue to change. For example, ifosfamide—a highly effective agent against sarcomas, which tend to strike adolescents and young adults—was once thought to all but guarantee sterility.
“For a long time, I had been telling teenage and young adult men that the first course of ifosfamide was very likely to render them sterile. Now, we have case reports of men who had doses of ifosfamide that presumably would have rendered them sterile but who—10, 15, 20 years later—appear to have recovered some fertility,” Dr. Hughes said. “Now I tell these guys, ‘You cannot count on the chemotherapy to be birth control for you, but when you want to have a child, you’re likely to have a great deal of difficulty having one that’s biologically your own.’”
The infertility risks of some newer therapies also remain unclear. For example, many targeted therapies inhibit enzymes, but all the actions of those enzymes are not always known.
“One of the misconceptions about targeted therapies is that they’re going to hit just their cancer targets. But some targeted therapies are going to hit multiple targets,” said Anna Franklin, M.D., an assistant professor in the Division of Pediatrics. “We know that these molecular targets are on the cancer, but they’re often in other places as well.”
In some cases, those other places are integral to fertility. For example, the ovaries of women receiving tyrosine kinase inhibitors such as imatinib do not respond to stimulation with hormone therapy; as it turns out, imatinib inhibits an enzyme critical to presenting the hormones to the ovaries.
Because decisions about fertility preservation must be made before treatment begins, discussions about the infertility risk posed by treatment tend to happen early.
“Typically, I bring up the risk of infertility in that first conversation about the diagnosis. Sometimes that’s not an easy conversation because people haven’t thought about it,” Dr. Franklin said. “And sometimes patients are so overwhelmed by their cancer diagnosis that they don’t hear about the risk of infertility.”
Noting that religious, cultural, and moral factors all may play into the decision, Dr. Franklin said, “It’s sort of a simple yes-or-no question—do you want to have children?—but it often leads to many other questions that must be answered.”
The conversation about infertility risk can be more difficult if the patient is a minor. Part of this difficulty stems from the awkwardness some parents and their children experience when discussing reproduction and sex, but it can also stem from differences in what parents and their children desire.
“Some 16-year-olds might have a very strong opinion about what they want their future to be like, but their parents are the medical decision makers,” Dr. Hughes said. “Sometimes, there’s a disparity between what the parents want for their child and what that adolescent wants for his or her future.” Regardless, he said, “The child really needs to assent to the therapy or the choice being made. The parents may decide, but the child in essence must agree to cooperate.”
To help address the fertility needs of its patients, MD Anderson recently hired Terri Woodard, M.D., an assistant professor in the Department of Gynecological Oncology and Reproductive Medicine. Dr. Woodard, a board-certified reproductive endocrinologist, splits her time between MD Anderson, where her role is purely consultative, and Baylor College of Medicine, where all procedural work—in vitro fertilization, oocyte cryopreservation, and even sperm banking—is performed.
“The beautiful thing about this partnership is that it offers patients streamlined access to an academic program with research support, great lab facilities, and a track record of doing well with infertility,” Dr. Woodard said.
At MD Anderson, Dr. Woodard talks to patients at all steps of their cancer journey, whether they have just been diagnosed and want to talk about strategies to preserve their fertility, are being treated for their disease and want to know what to expect later on, or are many years out from treatment and want to know about their fertility status. Most of her work centers on female cancer patients.
“All patients who are of childbearing age are eligible for a consultation,” Dr. Woodard said. “Regardless of whether they have children already or how sick they are, patients really deserve to know what’s happening to them and what their risks are. If there is anything that could be done to preserve these patients’ fertility, they should have access to those options. Even some of the sickest patients tell us, ‘I know I’m not a candidate for doing this, but I’m glad you addressed that portion of me that always wanted to become a mother.’”
The first step in the consultation is to assess the person’s risk for infertility. To this end, Dr. Woodard often requests that patients undergo ultrasonography and blood tests to determine whether they are among the 15% of people in the general population who already have fertility issues. For these patients, she may advocate a more aggressive approach to fertility preservation.
After determining infertility risk, Dr. Woodard assesses the patient’s medical history and treatment plan to identify options for fertility preservation. The timing of the cancer treatments may dictate whether fertility preservation is possible.
Dr. Franklin said, “One of the issues we run into is that patients need to start treatment rather urgently. When you tell patients that you can preserve their fertility but will have to hold off on treating their cancer for several weeks, some of them will get very nervous.”
“Sometimes you just don’t have much of a choice,” Dr. Hughes said. “When a patient comes in and is already very ill, you may have to begin treatment as quickly as you can to fight back the malignancy, and there is not much time to address infertility risk.”
Finally, after discussing the risks and costs of each option as well as the time required to perform it, Dr. Woodard talks about what steps might be taken after treatment if patients choose to forgo fertility-sparing measures beforehand.
“Some people will come through cancer therapy and have normal fertility and get pregnant on their own the natural way; other people will need help; and other people will have permanent infertility,” Dr. Woodard said. For patients likely to have permanent infertility following cancer treatment, she will talk about options including adoption, using a gestational carrier, and using donor eggs or donor sperm. “I tell these patients that they might have to re-frame how they think about becoming a parent, but if they want to be a parent, they still can be,” she added.
For men and postpubertal adolescent males, the approach to preserving fertility is relatively straightforward: these patients are referred to a sperm bank, where they provide a specimen that is subjected to semen analysis and infectious disease testing and then frozen and stored until they wish to have children. The longest time between banking sperm and using the specimen for successful in vitro fertilization is 25 years.
Not all males are able to easily provide viable sperm, however. In men who are unable to ejaculate—because of nerve damage from their cancer or its treatments, for example—electroejaculation may be used to procure a specimen. In males whose ejaculate does not contain sperm, testicular sperm extraction using fine-needle aspiration may be used.
Despite recent advances, harvesting a woman’s eggs remains a greater challenge, especially in cancer patients. For women and postpubertal females, the standard of care for fertility preservation now includes freezing the harvested eggs alone (oocyte cryopreservation) in addition to inseminating the harvested eggs and freezing the resultant embryos. Before any eggs can be harvested, however, the ovaries must first be stimulated with hormones to produce multiple eggs. This process takes 2–3 weeks, putting egg harvest and preservation beyond the reach of some patients who need to start treatment immediately.
One method that may provide an option for women who need immediate cancer treatment is ovarian tissue cryopreservation (OTC). In OTC, the part of the ovary that contains the eggs is surgically removed and frozen; after cancer treatment has ended, the tissue is thawed and reimplanted. Because OTC can be completed in a matter of hours, it can be used in patients who must start treatment immediately. In addition, because strong, estrogen level–elevating fertility medications are unnecessary with OTC, the procedure is theoretically a safer option in women with breast cancer or other hormone-sensitive cancers.
However, OTC is extremely new and experimental; to date, only about 30 live births from women with reimplanted egg-containing ovarian tissue have been reported. Still, OTC is the only fertility-preserving option for prepubescent girls.
Similarly, testicular tissue cryopreservation, a fledgling technology in which spermatogonial stem cells are isolated from harvested testicular tissue, may one day enable prepubescent boys who require fertility-threatening cancer treatments to father children in adulthood. “The thought is that those stem cells can be matured outside the body and then be used for in vitro fertilization,” Dr. Franklin said. To date, however, no live births have resulted from using this technology.
For both OTC and testicular tissue cryopreservation, one concern is that removing tissue before treatment and reimplanting it after treatment has the potential to reintroduce the cancer. However, refining methods to screen the harvested tissues before reimplantation may address this concern.
“In girls with leukemia who had ovarian tissue harvested, researchers were able to do polymerase chain reaction tests for specific chromosomal translocations found in the patient’s leukemia cells. Finding those translocations in the ovarian tissue would be highly suggestive that there are leukemia cells in the ovaries,” Dr. Franklin said. “The same concern exists with spermatogonial stem cells. However, in boys with leukemia who had testicular tissue harvested, researchers were able to separate the spermatogonial stem cells from the leukemia cells through flow cytometry.”
Just as important as addressing infertility risk before cancer treatment is monitoring fertility after therapy. Women who have undergone cancer treatments that would likely affect their ability to have children may experience menopause sooner than women who have not had such treatments. Therefore, closely following these patients for signs of early menopause and deciding whether to pursue egg harvest is essential.
The conversation about the effects of treatment on fertility bears repeating even after therapy has ended, Dr. Woodard said, because then patients who were overwhelmed with information and emotion at that initial discussion of their diagnosis may be more receptive to the information and more apt to remember it.
“I don’t think physicians always do a good job of communicating to patients that they should monitor their fertility after their cancer treatment,” Dr. Woodard said. “I’ve had quite a few patients who have come in on both extremes: some had no clue that they would have a fertility problem, and others assumed they couldn’t get pregnant because they had chemotherapy.”
In addition to revisiting the potential fertility issues stemming from treatment, Dr. Woodard recommends that 1 year after patients complete therapy, they undergo ultrasonography and blood tests to assess fertility. Decisions about future monitoring and potential treatments can then be made.
“We’re seeing these patients in our survivorship clinics and counseling them that we can check their fertility status and make decisions based on that,” Dr. Franklin said. “Do we need to think about harvesting some eggs now, or can we wait a few years? Or do we just need to monitor their fertility and assess it thoroughly when these patients are ready to have children?”
The financial burden of preserving fertility after cancer treatment can be significant. For men who bank their sperm, the cost of the semen analysis, infectious disease testing, and 1 year of storage is around $650. For women who elect to freeze embryos or eggs, the cost is much higher, on the order of $15,000 per in vitro fertilization cycle.
“Women who are infertile for reasons other than cancer treatment may have been saving up for something like this. But cancer patients don’t necessarily think about fertility preservation, and then they need to do it fairly rapidly so they can start their cancer treatment. They don’t really have the option to plan for the expense,” Dr. Franklin said.
Some patients’ insurance plans cover these costs, but these tend to be the exception, not the norm—for now. The American Medical Association recently adopted a resolution stating that insurance should pay for fertility-preserving procedures. As in patients who require breast reconstruction following mastectomy, a treatment that causes infertility has resulted in a defect that has huge implications for the patient’s quality of life. With the increasing number of young cancer survivors, it may be only a matter of time before fertility-sparing treatments for these patients are covered by insurance.
“Some studies have shown that cancer-induced infertility can be as stressful as the cancer diagnosis itself and that the stress can persist many years after the patient has been cured. There can be a lot of regret in that, especially for people who had no idea that they might have had options to have their own biological children,” Dr. Woodard said. “As part of our informed consent process, we’re telling people that we’re giving them drugs or radiation that might cause these problems, and it’s our responsibility to offer solutions and make them available and acceptable for everyone.”