When Erica Avello’s son Frankie Knowles woke up screaming in the middle of the night, the first thing she did was take his temperature. “I thought the thermometer was broken,” Avello says. “His forehead was freezing, and his temperature was 94 degrees.”
After complaining that his head hurt, Frankie, then six, vomited and “became nonresponsive and just kind of floppy,” Avello says. She and her husband rushed Frankie to the hospital closest to their Downingtown, Pennsylvania, home. “They did a CT scan and said his brain was bleeding.” Frankie was transferred by helicopter to Delaware’s Alfred I. duPont Hospital for Children, where he underwent more than a week of testing and scans.
“His temperature was so low,” Avello, 40, says, “because the tumor was affecting the area of the brain responsible for temperature regulation.” Frankie was diagnosed with Pilomyxoid astrocytoma — a rare form of cancerous brain tumor that only develops in pediatric patients. It had already metastasized to four different sites in his spine.
For his parents, those days were a horrifying whirlwind of meetings with a whole team of doctors to develop an aggressive treatment plan for Frankie. Before they jumped into a chemotherapy regimen, though, they met with Danielle Morley, Nemours’ fertility preservation coordinator.
“She came to see us and said, ‘You might want to consider that someday Frankie is going to be a grown-up, and he might want to have kids,’” Avello recalls. One of the potential long-term effects of the treatment Frankie was set to undergo is a loss of fertility, and Morley was there to talk options.
“It’s amazing that survival rates have increased so greatly; now we need to be looking at ways to ultimately increase their quality of life.”
Oncologists have been having conversations about fertility preservation with people preparing for chemotherapy and radiation for a long time. Many common cancer treatments threaten future fertility, so it’s normal for women to consider freezing their eggs or embryos, or for men to preserve their sperm, before undergoing treatment. Until recently, there were no such options available for children with cancer who have not entered puberty, most of whom won’t be thinking about biological children for at least a couple of decades.
But new, promising research into the cryopreservation of ovarian and testicular tissue is changing the conversation. A growing number of institutions across the country and around the globe are offering surgical and laparoscopic procedures to remove ovarian or testicular tissue from prepubertal patients. The tissue is then cryogenically frozen, in anticipation of one day being reimplanted in the same patient, and stimulated to produce viable eggs, sperm, and hormones. Reported cases of healthy, live births in both primates and humans have made fertility a hot topic in pediatric oncology programs nationwide.
“Danielle [Morley] explained that this procedure he was a candidate for is still experimental, but in 20 or 30 years they might be able to take his tissue and turn it into something,” Avello says. “At that point, I was so sleep deprived I just said okay, let’s do it.”
At the time, Nemours didn’t have the capacity to perform the tissue extraction, so Avello and her husband took Frankie to another hospital, in Pittsburgh, where doctors placed Frankie under general anesthesia, sliced a hole in his scrotum, removed a small, wedge-shaped piece of testicular tissue, and stitched him up.
Today, Frankie is a lively eight-year-old who’s into karate and Disney movies. “He doesn’t really remember that it happened,” Avello says. “But we did talk to him about it — we explained that, someday, when he’s grown up, he might want to be a daddy, and he might need this to help him.”
Survival rates for childhood cancers have risen rapidly in recent decades. In 2016, there were an estimated 15.5 million cancer survivors in the United States, close to half a million of whom were first diagnosed before the age of 20. The National Institutes of Health (NIH) reports that today, thanks to advances in treatments, 84% of children with cancer are alive at least five years after being diagnosed. The ever-improving odds are driving a growing body of research into the issues — both medical and mental — that accompany survivorship.
Chemotherapy works by using an alkylating agent to target fast-dividing cancer cells, breaking down their DNA and affecting their ability to multiply. But chemotherapy also impacts other, healthy, quick-dividing cells. That’s why it typically causes hair loss, low blood cell counts, and nausea. Those side-effects are temporary; they disappear once the chemotherapy treatment ends.
However, in child cancer patients who are still growing, the whole body is made up of cells that are dividing more quickly than they do in an adult. Because of the damage chemo does to these cells, many kids experience what doctors call “late effects” a number of years after their cancer has been declared in remission. Commonly reported late effects include developmental delays, thyroid problems, stunted growth, bone and muscle issues, heart disease, and decreased lung function, among others. Many common chemotherapy drugs also have a significant impact on sexual development.
“It’s really nice to hear people saying his future is bright, he’s going to beat this, and become an adult…I like talking about Frankie as a 30-year-old.”
Some rapidly dividing cells reliably bounce back post-chemotherapy (blood cell counts rise, and hair and stomach lining grow back), but others — like the stem cells that divide to produce sperm and the hormones testosterone and estrogen — never recover. The same is true in adults undergoing chemotherapy, but when it comes to preserving fertility, people who have gone through puberty tend to have more available options. Sperm banking is a reliable, standard-of-care method, but it only works for boys and men who have mature sperm to bank. For women, egg retrieval and freezing have become commonplace, but, again, it’s only a viable option for those who’ve gone through puberty, and have started releasing eggs. In addition, the process of egg freezing can take up to a month. Many children with cancer can’t wait that long, says Morley.
“In the adult world there can be a couple of weeks between diagnosis and the start of treatment,” Morley says. But with kids, “we tend to start treatment a lot quicker. Kids can get seriously sick much faster, because a lot of times these are more acute, quicker-moving cancers. We’re limited in the time frame that some of these patients have available.”
That’s why, at Nemours, Morley steps in right away to counsel parents through the decision-making process. If their child is a candidate for tissue cryopreservation, and the parents decide they want to give it a try, they need to move fast.
The existence of programs like Nemours’ — and coordinators like Morley — has drastically improved families’ access to cryopreservation, says Leena Nahata, MD, an endocrinologist at Nationwide Children’s Hospital in Ohio and chair of the Pediatric Initiative Network, an arm of the Oncofertility Consortium.
“It used to be the model that if a family was concerned or brought up the question of fertility, we’d start thinking about options or making some phone calls, which was often a major barrier because these options need to be done fairly quickly,” Nahata says. “There’s an onslaught of things that need to happen in a short amount of time, and it takes a lot of stakeholders; the primary oncologist needs to be on board, the family, whoever’s doing the procedure. Whenever possible we’re also trying to coordinate it with another procedure, like a line placement, so this can all be done under a single anesthesia.”
In 2015, a report in the medical journal Human Reproduction detailed the case of a young woman from the Republic of Congo, then living in Belgium, whose severe sickle cell anemia necessitated a bone marrow transplant from her brother. A successful transplant requires that the immune system be completely suppressed to prevent rejection — typically using chemotherapy or radiation.
The girl was 13, but hadn’t yet gotten her period when doctors removed and froze fragments of her right ovary. After chemotherapy and a successful transplant, the patient received hormone replacement therapy at 15 to induce menstruation. A decade later, in an effort to restore her fertility, a team led by Isabelle Demeestere of the Fertility Clinic and Research Laboratory on Human Reproduction at Belgium’s Erasme Hospital grafted 15 pieces of the previously frozen ovarian tissue onto the patient’s remaining ovary and other sites in the body. The transplanted tissue began to grow follicles that contained maturing eggs. She started to menstruate, and two years later got pregnant and gave birth to a healthy baby boy.
There have been more than 130 documented live births to mothers who have had ovarian tissue cryopreserved and reimplanted, but the patient in Belgium was the first case where the tissue was removed prior to getting through puberty.
Research is advancing on the male end of things, too. A Canadian study published in December of last year helped scientists begin to understand exactly how chemotherapy affects the integrity of DNA in sperm, even when that sperm is produced after the treatment ends. And in March of 2019, a team of researchers at the University of Pittsburgh published a landmark study in the journal Science.
The researchers cryopreserved the testicular tissue of a prepubertal monkey. When it was reimplanted, the tissue matured and produced sperm which was then used to fertilize an egg that ultimately resulted in the birth of a perfectly healthy baby monkey. The researchers hypothesize that the results could be repeated in humans, with a few caveats. A major one is the fact that the tissue collected, particularly from pediatric patients with leukemia, lymphoma, or testicular cancer, could potentially contain cancer cells, making reimplantation dangerous.
On the other hand, it has the potential to work well in people with tumors such as sarcomas and neuroblastomas, and those who receive bone marrow transplants for conditions like beta-thalassemia and sickle cell anemia. That second category encompasses more than 60% of the patients — including Frankie Knowles — who’ve already frozen their testicular tissue at the Fertility Preservation Program in Pittsburgh or at affiliated sites, including Children’s National Medical Center in Washington, D.C., Lurie Children’s Hospital in Chicago, Cincinnati Children’s Hospital, Milwaukee Children’s Hospital, Children’s Hospital of Orange County, Mayo Clinic, and others. Most of those families pay annual fees ranging from $75 to $500 to have it stored in nearby cryogenic facilities. The potential uses for that tissue could ultimately go beyond the ability to have children.
“Testicles and ovaries have two jobs,” says Nahata. “They make sperm and eggs, but also hormones. [During chemotherapy,] testosterone production and estrogen production can be compromised.” Without adequate testosterone, it can be a struggle to build and maintain bone and muscle mass. A lack of estrogen forces young women into early menopause, which increases the odds of osteoporosis and heart disease. Nahata is hopeful that cryopreservation and reimplantation techniques could ultimately be used to treat that.
“In an ideal world, we’d be able to reimplant that tissue at the time of puberty, and have it be functional long enough to get through puberty naturally and be able to produce children,” she says. “At this point, we’re not all that clear on the long-term function, and it’s all still very experimental.”
Finding new ways to address long-term fertility issues may also have a positive impact on the mental health of young people who survive cancer. “It’s a big source of depression in survivorship as these things emerge in combination,” Morley says. “It’s amazing that survival rates have increased so greatly; now we need to be looking at ways to ultimately increase their quality of life.”
For parents like Avello, even discussing the potential of these now-experimental procedures represented a welcome beacon of hope. “It was pretty cool to be talking about Frankie as a grown-up,” she says. “It’s really nice to hear people saying his future is bright, he’s going to beat this, and become an adult. That’s a really, really nice thing to think about when everybody else is saying, ‘chemotherapy, radiation, tumor.’ I like talking about Frankie as a 30-year-old.”
It’s not uncommon, Morley says, for parents to cling to the idea of their child’s faraway future when the “life-and-death stuff” is dominating the present.
“It’s like the one positive thing they’re hearing,” Morley says. “Most of the conversations they’re having are about survival rates and chemo and side effects, and that’s all so hard to process. But we’re giving them the option to actually do something about it. They see this as a glimmer of hope because we’re telling them we see their kids getting through this.”
That’s not to say that a cryopreservation procedure is the best option for every family. Sometimes, treatment needs to begin too quickly, or the patient is too unstable to undergo the extraction. Religious beliefs can play a role. For some, the procedure is still too experimental to warrant an extra surgery. It can be a complicated choice, says Karen Wohlheiter, PhD, a psychologist at Nemours.
“They’re in the process of making a lot of decisions about their child’s care overall, this seems like a big and heavy decision, and in most cases, unfortunately, they need to make it right away,” she says. “Where I come into play is that there can be a lot of associated guilt if they decide not to do it. I think you want for your child what you have, and to be able to give them every opportunity that you can, and it can feel really devastating that you’re ‘taking away’ an opportunity. Cryopreservation is highly experimental, but it’s the one option available. That can be really tricky for families because there’s no proof that it will work in the future.”
Even if the science weren’t theoretical, the future still is; and that kind of abstract decision-making can push parents to conflate their child’s theoretical future with their own reality.
“I’ve had parents of very young children — two- and three-year-olds — be devastated by the news that their child may end up facing infertility,” Wohlheiter says. “There might be a presumption that you’re not thinking about that stuff when your kids are that age, but these parents are in that early phase of having a child and all the wonderful things that come along with it. For them to think their child may not have that, or the option to have that, can be very difficult.”
Some parents also wrestle with the idea that, by making this decision for their young child, they’re taking away some of that child’s autonomy.
“It seems like there’s a major weight that comes with a parent making that big decision for a child,” Wohlheiter says. “There might be a 17-year-old child saying, ‘Yes, I’ll do sperm banking,’ or, ‘I want to do egg retrieval, and I understand the risk of delaying treatment.’ When you’re making the decision to do tissue preservation for your five-year-old, without them being able to give you any real input, that can be really challenging. It’s really important for parents to have support during that time.”
At Nemours, and many of the other sites offering cryopreservation options, meetings with a family psychologist are a crucial part of the process — whether families decide to move forward or not.
“It’s about helping parents have confidence in their decision-making,” says Wohlheiter. “And, moving forward, accepting and acknowledging that they made the best decision for their child at that time. There’s so much uncertainty, and so much, ‘what if I made a different decision.’ We work on not focusing on the what-ifs.”
For families that are choosing to move forward with cryopreservation, the whole enterprise is a practice in “what ifs.” Essentially, parents are making an investment in science that doesn’t totally exist yet — not to mention a potentially significant monetary one; if they live in a state where experimental fertility procedures aren’t covered by insurance, costs can top $10,000.
“There’s a lot of unknown that comes along with cryopreservation, and it’s hard to say, ‘We want you to have faith and believe that this is going to work,’” Wohlheiter says. But as the procedures become more commonplace, and research into the long-term viability of fertility restoration moves forward, she believes more families will be willing to bet on progress.
“I think there’s a much greater openness to talk about fertility treatments like sperm banking and egg harvesting,” she says. “People are more and more aware of those options. I think the vocabulary for cryopreservation and what that will look like just isn’t quite there yet.”
Nahata is confident that both popular opinion and technology will catch up, and notes that some programs are now offering cryopreservation to populations with illnesses like Turner Syndrome, a genetic condition that can cause early menopause and infertility, in addition to cancer patients. While she cautions that outcomes in one disease population may not translate exactly the same way to others, early research is promising, and tissue is being preserved from patients as young as six months old.
Ethical questions persist, too. There are some significant gray areas: If a patient should die, for instance, there’s not always a clear directive for what happens to their preserved tissue. Adolescents and teenagers are generally considered able to offer “informed consent” prior to pursuing fertility preservation, and Morley says patients old enough to grasp the conversation are involved in the decision-making. But the parents of younger children, toddlers, and infants often face what she calls “moral and ethical difficulties” in making that choice for them.
While there are still an enormous number of unknowns, and the field of cryopreservation still has years of animal and human testing, peer-reviews, and FDA approvals ahead of it, Wohlheiter believes that by the time today’s pediatric patients are ready to have their tissue reimplanted, there will be available science we can hardly fathom today.
“It’s amazing that the technology to preserve this tissue exists,” she says. “One of the things we talk to families about is that the field has advanced so incredibly in just the last 15 years. By the time their child is ready to use the tissue, it’ll be even better.”
After an ineffective first round of chemotherapy, Frankie successfully completed a second protocol in November. He’s currently off treatment, and awaiting an MRI just after the new year.
“The tumors shrank a bit on the second protocol, and they’re still in there — four in his spine and one in his brain — but they’re stable,” Avello says. Frankie’s cancer exclusively affects children; if it remains stable until he reaches adulthood, it will stop being a threat. That, Avello says, is when he’ll have the option, if he wants it, to use his cryopreserved tissue.
“It makes me feel good that it’s there because I didn’t want cancer to take another thing from him,” she says. “I don’t know that he’ll want to have kids, but I wanted him to have that choice to make for himself. I’m not going to decide that for him, but I certainly didn’t want cancer to decide it for him.”
In the meantime, in a deep-freeze facility in Pittsburgh, the family’s investment in their son’s future — and in the science of tomorrow — is safe and sound.