Dana-Farber's Work to Improve Fertility Preservation for Cancer Patients
February 14, 2024
By Robert Levy
More than 30 years later, Dana-Farber doctors still tell the story of the patient with an ovary behind her armpit.
The patient came to the Institute after experiencing monthly pain in her shoulder area. When she met with her oncologist in the David B. Perini Jr. Quality of Life Clinic for cancer survivors, she mentioned the unlikely location of her ovary, and that it was no accident of birth.
Years earlier, as a girl, she had undergone surgery, chemotherapy, and radiation therapy for Wilms tumor, a childhood cancer of the kidneys. To protect one of her ovaries from the damaging effects of radiation, a surgeon had moved a slice of it to her shoulder muscles, well out of the radiation field, and connected it to her blood supply. She and two other young patients who had undergone the procedure had a normal onset of puberty and normal menstrual cycles thanks to the hormones released by the relocated ovaries, which produced mature eggs for about 15 years. Though none of the patients chose to try to conceive a child by in vitro fertilization, the fact that their bit of ovary continued to work suggested a new approach to retaining ovarian function.
The ovarian relocation from pelvis to armpit, known as an axillary oophoropexy, is no longer performed, but it demonstrates that even before assisted reproductive technologies became widespread, doctors were exploring ways to preserve potential fertility in patients treated for cancer. Today, there are multiple ways to preserve fertility, but the decision, made during the stress of an unexpected cancer diagnosis, can be complicated.
Fertility After Cancer Therapy
Cancer therapies can harm fertility — the ability to conceive a child — in a variety of ways. Whenever cancer itself or the treatment of the disease affects the organs or glands involved in reproduction, fertility may be at risk. The extent of that risk depends on a variety of factors, including the patient's age, the type and stage of the cancer, and the type of treatment.
Some chemotherapy drugs, for example, can cause the ovaries to stop releasing eggs and may lower the number of eggs in the ovaries. Certain chemotherapy agents can slow or stop sperm production. Radiation therapy to the abdomen, pelvis, or spine can damage nearby organs like the uterus or prostate gland; and radiation to the brain can affect the hypothalamus, a part of the brain that helps signal the ovaries to make estrogen and ovulate. Drugs that block the production of estrogen can disrupt or halt the menstrual cycle. The effect of these treatments on fertility may be temporary or, as in the case of surgery to remove reproductive organs and tissues, permanent.
In some cases, these treatments can be modified to reduce their impact on fertility. Surgeons always try to save as much healthy ovarian tissue as possible when removing tumors in the ovary or surrounding tissue. Leaving behind healthy parts of the cervix or uterus in patients with low-risk cancers of these organs may maintain patients' ability to carry a child.
For most patients, though, fertility is preserved with techniques that protect reproductive organs or germ cells — sperm and eggs — from the damaging effects of cancer therapy, sometimes by removing them from the body entirely so that the germ cells never encounter the chemotherapy or radiation. For males past the age of puberty, banking sperm before treatment is the main option. (Researchers are studying the feasibility of freezing testicular tissue from young patients. It's not known whether such tissue, thawed and reimplanted after treatment, will produce healthy sperm.)
For women and girls past puberty, the options are more complicated. They include freezing eggs or embryos before treatment; suppressing the ovaries with medication during treatment; shielding the ovaries or moving them to another part of the body to shelter them from radiation therapy to the pelvis; and freezing the ovaries or slices of ovarian tissue for reimplantation when treatment is complete.
All of these options can lead to successful births, but each has certain limitations. Freezing eggs or embryos, for example, requires the harvesting of eggs, which can take two weeks or more and may not be feasible for patients who need to begin treatment quickly. There are also concerns that, if cancer has spread to a reproductive organ, removing and reimplanting it after treatment might reintroduce the disease. And then there's the cost: Freezing anything — sperm, eggs, embryos, ovarian tissue, or testicular tissue — entails long-term costs that typically aren't covered by insurance. The costs of egg or tissue removal may not be covered, either.
Issues like these — as well as the broader question of whether to utilize fertility preservation and, if so, what type — typically can't be put off. Patients and their families usually have a very short time in which to make decisions — about their ability to become a parent and have a family — that can profoundly affect their future. Oncofertility programs like those at Dana-Farber/Boston Children's Hospital Cancer and Blood Disorders Center and Dana-Farber Brigham Cancer Center not only provide services including sperm banking and egg and embryo freezing, but also counsel patients and families on their options and opportunities.
Early in my career, I saw how young women with breast cancer were suffering – patients who, in addition to having a life-threatening illness, were facing infertility.
Improving Fertility Preservation Options
Fertility preservation has become an option for many patients not only because of techniques for saving reproductive tissues and cells, but also because of advances in cancer treatment itself. In the days when cures were few and survival times were often brief, patients grieved their potential loss of fertility even as they girded to fight their disease. Now that patients can often become parents, fertility preservation has become an intrinsic part of cancer care, as much a concern as patients' mental and physical well-being.
It was that awareness that led Ann Partridge, MD, MPH, a breast cancer specialist and director of Dana-Farber's Adult Survivorship Program, to focus on fertility issues as both a clinician and a researcher.
"Early in my career, I saw how young women with breast cancer were suffering — patients who, in addition to having a life-threatening illness, were facing infertility," Partridge says. "The loss of the future one anticipates for oneself — including being a parent — can be devastating. It became clear to me that fertility is something people grieve when it's gone, and that we weren't doing enough to help them through that process or to let them know about options for retaining their fertility."
At Dana-Farber and its partners Boston Children's Hospital and Brigham and Women's Hospital, researchers are studying fertility preservation from multiple angles. They're exploring how patients weigh fertility issues when deciding on treatment and are cataloging the effects of different cancer therapies on fertility. Other investigators are examining how well fertility preservation strategies work: are patients able to conceive after having their tissue or germ cells stored? Still others are developing computer applications to help patients anticipate the impact of treatment on their fertility.
Opening a Conversation About Fertility
When options for fertility preservation were few and unreliable, physicians and care providers were often reluctant to broach the subject with patients — a reticence that persisted, in some quarters, even after preservation techniques improved. Partridge has led several studies to assess how important fertility is to young women with breast cancer and how those concerns affect the decisions they make about treatment.
Dana-Farber investigators surveyed women with breast cancer about their infertility concerns and how they addressed those concerns.
One study, which surveyed 657 young women with breast cancer, found that 57% had been concerned about becoming infertile from treatment and 29% based their treatment decisions, at least in part, on those concerns. Seventy-two percent of the women reported discussing fertility concerns with their doctors, and 51% felt their concerns were addressed adequately.
"Fertility is an important issue for young women that needs to be addressed by clinicians," Partridge says. "We want to ensure patients have a voice: even when it isn't practical for them to go on to have a baby, they need support in coming to terms with that loss."
Concerns about future fertility are compounded by the anxiety of a cancer diagnosis itself. In some cases, the most powerful treatments are also the most damaging to fertility. How to balance one's potential to have a family with the immediate imperative of survival or cure? Such questions are especially challenging in the case of very young patients, for whom parenthood may be many years away.
To understand how parents of young patients approach these issues, and how they weigh the effectiveness of treatment against potential long-term side effects such as fertility loss, Katie Greenzang, MD, EdM, of Dana-Farber/Boston Children's Cancer and Blood Disorders Center, has conducted several studies based on surveys of hundreds of parents.
"We found that fertility is a major consideration that many patients and parents think about when embarking on therapy," Greenzang remarks. "But we also found that both parents and physicians are willing to accept a high risk of infertility in exchange for an improved chance of cure — it's one outcome people are most willing to trade, actually.
"I think part of the reason for that is that people know there are many ways to approach building a family in the long run. So even though fertility is something they're very concerned about and want to do everything they can to preserve, they recognize that there are a variety of ways of addressing it."
Tools for Counseling
Dana-Farber researchers have undertaken a variety of projects to equip clinicians with tools — information and techniques — to counsel patients in fertility preservation.
A prime example is a comprehensive review that summarizes the fertility risks associated with cancer treatments in both children and adults. The paper was prompted, in part, by the increased awareness of the importance of fertility preservation and the growing availability of preservation techniques.
"There was a sense that the pendulum may have swung too far in some cases — that preservation was being recommended for patients at very low risk of fertility loss," says Dana-Farber's Philip Poorvu, MD, of the Breast Oncology Center at Dana-Farber, who led the review with Ann Partridge. "Our paper documented the risks of fertility across all major cancer treatments. We categorized the risk of fertility loss as low moderate, or high, and put all the information in one place for practicing clinicians." Since the review was published in 2019, it has become a go-to guide for cancer physicians around the world.
Current research into the fertility effects of cancer treatment focuses on subtleties not captured by previous studies. For example, many young women with early breast cancer develop treatment-related amenorrhea (TRA), a cessation of menstrual periods that can signal long-term loss of fertility. It hasn't always been clear, however, which patients are at greatest risk for the condition.
To find out, Poorvu and Partridge analyzed data from the Young Women's Breast Cancer Study, a large study of more than 1,300 patients under age 40 diagnosed with breast cancer between 2006 and 2016. "We found that younger age was, essentially, protective: women under 30 had a significantly lower risk of amenorrhea than those age 36-40," Poorvu relates. "We also found that women with a normal or lower body mass index [a measure of body fat] were more likely to develop TRA. The biological mechanism behind this isn't clear but may inform future research."
Much remains to be learned about the long-term effects of treatment for certain childhood cancers, especially those which, until recently, had low survival rates. High-risk neuroblastoma, a cancer of immature nerve cells that mainly strikes young children, is a case in point.
"Survival rates for this disease have gone from less than 10% in 1985 to about 60% today," says Lisa Diller, MD, of Dana-Farber/Boston Children's Cancer and Blood Disorders Center. To understand how treatment can affect survivors' health over time, Diller is co-leading a study tracking almost 400 survivors of high-risk neuroblastoma. Dubbed the LEAHRN study (for Late Effects After High-Risk Neuroblastoma), it hopes to draw connections between survivors' characteristics – their age when diagnosed, the severity of their disease, etc. – the treatment they received, and the complications they've experienced.
"The participants, who received treatment at an early age, are now in late childhood or early adolescence," explains Diller, who is director of Dana-Farber's David B. Perini Jr. Quality of Life Clinic. "One of the issues we'll be looking at is whether survivors go through normal puberty. Among female participants, we'll be tracking levels of AMH, a hormone being studied as a possible indicator of early menopause. Those who might be at risk of early menopause may, as they enter their later teen years, choose to have their eggs harvested and frozen."
Researchers also have addressed the safety of fertility preservation techniques themselves. The process of collecting eggs for freezing, for example, can take a week or two, potentially pushing back the start of chemotherapy for breast cancer. It can also raise blood levels of estradiol, a hormone that, in theory, can stimulate the growth of estrogen-sensitive breast cancers. In a recent study, Partridge, Poorvu, Elizabeth Ginsburg, MD, the past director of Assisted Reproductive Technologies at Brigham and Women's Hospital, and other investigators compared breast cancer recurrence and survival in patients who opted for fertility preservation and those who did not.
"After adjusting for a variety of factors, we found there was no difference in either recurrence or survival rates between the two groups," Ginsburg says. "Stimulating the ovaries for egg collection is a safe option for women with breast cancer who are receiving chemotherapy damaging to the ovaries."
Setting Expectations
As doctors gain a more nuanced understanding of the impact of cancer treatment on fertility, they're working on better ways to communicate that knowledge to patients. For doctors like Greenzang, technology offers a way to help patients know what to expect from their specific treatment.
"When I've surveyed the parents of young patients, many wished they had received more information about the potential late effects of treatment," Greenzang explains. "They usually receive an information sheet for each chemotherapy drug their child is receiving but struggle to understand the risks associated with the treatment regimen as a whole. I'm working on developing a computer app that will lay out the risks of late effects, including infertility, for the precise course of treatment their child is receiving. It will indicate whether the risks are low, medium, or high, and describe what can be done before, during, and after treatment to screen for these problems or lower their risk of occurring." The app, currently in the development stage, is expected to be ready for testing next year.
As they work to improve communication with patients, researchers are also exploring one of the most basic questions about fertility in female cancer survivors: to what extent do they desire, and are they able, to have children in the years after treatment?
The findings are encouraging. One study, led by Partridge and Poorvu, found that in the first five years after treatment, 36% of 1,026 participants in the Young Women's Breast Cancer Study reported an interest in future biologic children. Among the 130 participants who attempted to become pregnant in that period, 90 conceived. (In the general population, infertility rates are about 30% for women in their mid-30s and 50% for those in their early 40s.) Within the entire group, there were 152 pregnancies and 91 live births.
"The results demonstrate that a significant proportion of young survivors are interested in pregnancy and that it remains an important issue for years after treatment," Poorvu observes. "While some treatments do pose a threat to fertility, and while some survivors aren't able to become pregnant, many can and do go on to build their family."
Similar findings emerged from a study led by Diller and Ginsburg. They surveyed female participants in the Childhood Cancer Survivor Study, which tracks the health of more than 30,000 childhood cancer survivors, and found that, as expected, long-term survivors had an increased risk of infertility (defined as trying to become pregnant for more than a year without success). But they also found that even though it took longer, on average, for them to become pregnant, a good percentage of the survivors eventually did.
"The message we took from these findings is that it's important for clinicians to get involved with these patients — to let them know that if we're proactive and provide treatment, many of them can have children," Diller remarks.