When a young person is diagnosed with cancer, both clinicians and caregivers advance an imperative obligation to save that blossoming life in the hope it will eventually bloom to its full potential. Yet, in that intense post-diagnosis period, physicians and parents sometimes make medical decisions for their young charge without full regard for/or complete understanding of the negative secondary effects of some powerful therapies. Case in point: certain toxic-yet-lifesaving therapeutics result in decreased fertility or the inability to have children as surviving patients mature.
Douglas Fair, MD, MS, FAAP, knows well the trauma some patients later experience upon learning of their infertility. "Some survivors report it was as devastating as their cancer diagnosis itself," said the Associate Professor at the University of Utah in the Division of Pediatric Hematology and Oncology and Co-Director of the Oncology Fertility Program at the University of Utah, Primary and Children's Hospital, and Huntsman Cancer Institute.
Fair's professional reach extends well beyond the patients and institutions he serves. His legislative work on the expansion of Medicaid coverage of fertility preservation in Utah is being modeled throughout the country. Due to his groundbreaking work in sounding an alarm and preventing therapy-induced infertility, Fair was honored as the winner of the 2022 Cancer Community President's Award.
"I think most people can agree that having a loved one, particularly a child or a young adult, with cancer is one of the great tragedies in life," said a reflective Fair. "Helping treat and guide patients and families through this tragedy is an incredible privilege. But oncologists must do a lot of hard things to patients to get the best outcomes and ideally cures. The great majority of cancer therapies still use 'cut, burn, and poison,' meaning surgery, radiation, and chemotherapy. A lot of therapies are good at killing cancer cells, as well as harming normal tissues. So, while this work is rewarding, it is also extremely challenging; it requires all parts of my brain and frankly my soul and my heart."
Fair estimates that at least 30 percent of pediatric and AYA cancer patients are at risk for some degree of infertility. "Keep in mind that we have 120,000 patients in the U.S. that are 39 years of age or younger diagnosed with cancer every year," detailed Fair. "The cure rates for pediatric and AYA cancer are greater than 85 percent now. So, we have done an incredible job at increasing the cure rates; however, we are still using a lot of toxic therapy to get those results.
"Radiation to the testes or ovaries or to a part in the brain called the hypothalamus and pituitary gland, where hormones are released, can put someone at risk for infertility, as can some types of chemotherapy," he continued. "We now have more than 500,000 survivors of childhood cancer living in the U.S. And the number of those that are being seen in a quality survivorship clinic and talking about all their risks for late effects, including fertility and hormonal function, is very, very small. This is something we just need to do better with, both nationally and internationally."
Discovering Oncofertility
Originally from upstate New York, Fair went to Albany Medical College, followed by a pediatric residency at University of Texas Southwestern. He eventually went to the University of Utah for a fellowship in pediatric hematology and oncology. He became interested in oncofertility because he simply noticed a problem.
"The problem was we were not getting our children and young adults at risk for infertility the fertility preservation services they needed. As I pulled at one thread to try to solve the problem, suddenly something else would pull out, another barrier would be identified. And then another, and another. So, we started chipping away at them one by one."
Perhaps the biggest barrier is the fact that oncologists are not having conversations pertaining to fertility often enough with patients and/or caregivers. "As oncologists, we are not trained in oncofertility-a new and burgeoning field," Fair stated. "Yet, we are the ones who diagnose patients and consider treatments."
There now exist a lot of options for fertility preservation for most patients who are at risk for infertility. "But when oncologists are not totally in the know as to what is available medically for their patients, that creates a huge barrier," Fair said. "Another one of the barriers is due to the fact this is a very time-sensitive issue. Often a patient is diagnosed with cancer and there is quite a rush to treatment. When a patient is diagnosed with cancer, they must go over that diagnosis and have this nuanced discussion about their risk for infertility and fertility preservation options, then make decisions affecting their future self-that's really challenging. Helping a patient navigate that base both factually and emotionally is also a challenge for oncologists."
When the patient is very young, some even unable to grasp the concept of human reproduction, the task is even harder. "When you're talking about young patients, adolescents, or even young adults, they haven't even thought about wanting to build a family later," Fair explained. "So, we're asking them to think about things that are developmentally ahead of where they are. Having to talk about that at an already emotionally charged and stressful time is another barrier.
"Additionally, it's been well-documented in research that while we're oncologists, we're also just humans, and there is sometimes reluctance with the awkwardness of talking about fertility or sexual relations. So again, the data's clear that we, as oncologists, talk about fertility and related issues less than we should. And part of that might just be because of the nature of the topic.
"I've had young males who haven't heard the term masturbation [a component of sperm collection in fertility preservation] outside of the context of school. And they certainly haven't talked about it with their families. Sometimes I'm the first one to openly discuss it with them," detailed Fair. "That's a tricky thing to navigate. This is not what oncologists are trained to focus on. I think we should be creating systems where there are oncofertility teams specialized in these nuanced conversations and available to sit down and talk about this very sensitive topic at the appropriate level of the patient and family."
How Can Fertility Be Preserved?
"There is inequity between the sexes in terms of fertility preservation options," admitted Fair as he began explaining the preservation processes. For post-pubescent females, eggs can be harvested and frozen for later utilization and implantation. "Based on their physiology and their anatomy, it is more of a complicated endeavor and more costly for female patients to preserve fertility than for males," he explained.
"One part of the process is the stimulation of the ovary. Once a patient has previously started their menses and has ovulated, reproductive endocrinology and infertility specialists can prescribe a 1-2 week series of hormone injections that tells the ovary to mature a lot of follicles into eggs. So instead of having one egg prepared once a month, with these hormone injections a lot of eggs become ready," he explained.
At that point, the outpatient female is put under anesthesia. A needle is inserted through the vaginal wall and, with ultrasound guidance, advances to where the ovary holds the matured eggs and extracts them. After special preparation, the eggs are frozen. The patient can then start cancer therapy.
For an adolescent, the entire process can seem frightening and personally invasive. "The age, maturity, and developmental stage of an adolescent or young adult are super important," Fair emphasized. "It is important they're not scared and have a good experience with a tough procedure. This is something that needs to be handled with great sensitivity."
But what about prepubescent female patients? "The standard of care is to offer those with moderate-to-high risk for infertility ovarian tissue cryopreservation," he explained. "We can take a piece of the ovary and cryopreserve that. Later, when the patient wants to try to conceive, that piece of tissue is thawed, reimplanted into the patient, and the hormones are released in the body through the blood supply. This ovarian tissue sort of wakes back up and says, 'I'm going to start maturing follicles.' Then we would go in and do that same egg retrieval process we spoke about earlier. A surgeon or a pediatric adolescent gynecologist would do this."
This is also an important option for those post-pubescent females who don't have the luxury of waiting 2 weeks prior to beginning therapy. "They might be so sick with their cancer that they don't have enough time for the hormone stimulation and egg retrieval," Fair stated. "This can be offered to them; it is a one-time procedure that can be done urgently and quickly. Years or even decades later they could use that ovarian tissue, then go through the process of reimplantation and egg retrieval."
Fair said for post-pubescent males whose testes are producing sperm, "...the most straightforward, cost-effective, easy but awkward option is masturbation; we call it sperm banking. They would go to an andrology clinic and produce samples. Collected sperm would then be frozen for later intrauterine insemination or IVF."
However, there are some post-pubescent males for whom masturbation is not possible. "I have some young adults who are just unable to masturbate. It can be due to stress, their body is not feeling well because they have cancer, or they might have a tumor that's compressing on the nerves that are requisite for erection and ejaculation," Fair described. "In that case, a testicular sperm extraction may be performed. With the patient under anesthesia, a urologist would surgically remove part of a testicle where sperm is found, then cryopreserve that sperm."
For prepubescent males, the analogous technique to the ovarian tissue cryopreservation would be testicular tissue cryopreservation. "But we have not had successful cases in humans," Fair stated. "However, in monkeys, we have been able to take prepubescent testicular tissue and reimplant it. It woke up and started making sperm. That sperm was then collected and used to inseminate and create a live birth. Again, this field moves by leaps and bounds every year, so we are hopeful."
Another a big component of oncofertility is enabling patients to consider fertility preservation, even in post-therapy survivorship. "There are sometimes options for fertility preservation after patients are done with therapy if they didn't have the opportunity or didn't want it before therapy," Fair explained. "We talk with young adults who might have had their cancer at the age of 4 and certainly weren't in a place to understand or appreciate fertility or their hormonal function.
"We also can help women understand their risk of premature ovarian insufficiency, the importance for their overall health of treating premature ovarian insufficiency, how to screen for that, and to understand there are treatments to help with the symptomatology. A lot of female cancer patients are at risk, but that happens years, even decades after they've finished their cancer therapy. So, if we don't have systems in place to help these patients both before and after their cancer treatment, then we're really missing an opportunity to help them."
Barrier of Cost
There are a variety of costs involved in fertility preservation. "For males, in the most straightforward case when sperm banking is utilized, the cost between preparation and cryopreservation is typically $200-$500," Fair said. "Here again, there is inequity for women. The cost for egg stimulation and harvest typically can be 10-, 20-, or even 30-fold for females (typically estimates are $10,000-15,000).
"So here is someone at 12, 16, 20, or 25 years old, diagnosed with cancer, and they must make this decision right away. It is uncommon that insurance companies cover any of this; most cancer patients will not have any fertility preservation coverage. So, most of these people must pay this straight out of pocket. It's unattainable for a lot of young adults. And for a poorer population, this would just be pie in the sky. There would be no way they could even consider it. It's heartbreaking. It's unfair and backward in my view. And that's something we're working on here in Utah."
Fair explained that, effective in July 2021, the University of Utah, a major health care provider/insurer covering 5 percent of the population in Utah, became the first in the state to cover fertility preservation. "So, as an employee, if I, my partner, or my children are diagnosed with cancer, they will have that coverage," he said.
With that very real progress and encouragement from the University, Fair decided it was time to petition the Utah state legislature for more widespread coverage of fertility preservation for young cancer patients. He presented data to show that such important coverage isn't too costly for the health care system.
"In fact, it's extremely cheap because having cancer as a child or a young adult is a rare occurrence. We're still just talking about a cost that is prohibitive for an individual, but for a system is just a drop in the bucket. That was the real argument," Fair explained. "And it is the just right thing to do. During legislative hearings, we had some moving testimony from patients about how fertility preservation coverage was life-changing."
The message resonated with lawmakers and they passed House Bill 192, which mandates that Utah Medicaid must cover fertility preservation. "Medicaid covers about 10 percent of our state population. So that's huge," Fair stated. His efforts also contributed to the passage of House Joint Resolution 8 to cover state employees (i.e., firefighters, policemen, teachers, and many others-about 6 percent of the state population) via their employment benefits package.
"We're super excited about that. That just passed and should come into effect in January 2024," said Fair with justifiable pride. He noted that another large health insurer in the state-Select Health-has come to the table and is going to start covering some fertility preservation as well.
Fair said the big takeaways from the work can be boiled down to two messages. "The first message is just so clear from the data: About 75 percent of young adults with cancer eventually want to have a family. Not being able to have children is the most important late effect of their cancer. Survivors report it as devastating," reprised Fair. "We also know that those who have lost their fertility or have low fertility are at increased risk of depression and feel they have lower self-worth.
"And then the second message is [that] there are things we can do about it right now. We don't have to wait for new advances; we can achieve preservation now. It can take some teamwork, some logistics to get the patient to a consultation with people who can discuss their needs, their risk for infertility, and the options that are available to them," Fair enumerated.
Valerie Neff Newitt is a contributing writer.