Updated fertility preservation guidelines from the American Society of Clinical Oncology now recommend oocyte cryopreservation as standard practice and emphasize the need for all health providers, not just oncologists, to educate patients about their childbearing potential.
In addition to updating data on egg freezing, “the panel thought informing patients about fertility preservation was something the whole health care team should have ownership of,” said guideline co-chair Alison W. Loren, MD, Assistant Professor of Medicine at the Hospital of the University of Pennsylvania Perelman School of Medicine. “Medical oncologists are often put in the position of quarterback, and we want ancillary providers, such as nurse practitioners and social workers to also play a role,” she said.
Other guideline updates in the article, now online ahead of print in the Journal of Clinical Oncology (doi: 10.1200/JCO.2013.49.2678) include the use of letrozole as a safe option for ovarian stimulation, the possibility of initiating stimulation at any time during the menstrual cycle, the apparent ineffectiveness of gonadotropin-releasing hormone analogs (GnRHa), fertility problems associated with BRCA mutations, and patient health disparities.
“I think the main way the guideline update will impact practice is to bring to the forefront the importance of fertility preservation to oncologists who perform surgery and those who give chemotherapy,” commented Steven Waggoner, MD, Chief of Gynecologic Oncology at the University Hospitals Case Medical Center and Case Western Reserve University. “It's important to remind treating physicians that fertility is a concern of both men and women with cancer, even when faced with potentially life-threatening disease.”
KUTLUK OKTAY, MD, FACOG
To update the 2006 guidelines, a subset of the original ASCO Expert Panel conducted a systemic review of the literature published from March 2006 through January 2013. A total of 222 new publications were evaluated, the majority of which were observational studies, cohort studies, and case series or reports, in addition to a few randomized trials. After the review, the panel decided that clarifications for the 2013 update were needed.
Cryopreservation No Longer Experimental
The American Society of Reproductive Medicine no longer considers egg freezing to be experimental, and the literature evaluated by the ASCO panel indicates that using frozen eggs results in success rates similar to those using unfrozen eggs.
With the earlier guidelines, not enough data existed to support the use of cryopreserving unfertilized oocytes, said Pamela N. Munster, MD, Professor of Medicine and Leader of the Developmental Therapeutics Program and Director of Early Phase Clinical Trials' Program at the Helen Diller Comprehensive Cancer Center at the University of California, San Francisco. “The success rate wasn't high enough.”
The newer technique of vitrification has resulted in the success rate of using frozen eggs for fertilization paralleling that of fresh egg cycles, said Edward Illions, MD, Director of Fertility Preservation at Montefiore Medical Center and Associate Professor of Clinical Obstetrics & Gynecology and Women's Health at Albert Einstein College of Medicine.
However, he added, egg freezing is not particularly beneficial if women need to start chemotherapy immediately or within a few days of diagnosis, as is the case with aggressive cancers such as leukemias and lymphomas.
If a referral occurs just before chemotherapy is to begin, the only option women have is to freeze some of their ovarian tissue, said the other co-chair of the ASCO guideline panel, Kutluk Oktay, MD, FACOG, Professor of Obstetrics and Gynecology, Medicine, Cell Biology and Anatomy and Pathology and Director of the Division of Reproductive Medicine at New York Medical College and Medical Director of the Innovation Institute for Fertility Preservation.
This process does not require ovarian stimulation but is still experimental, he cautioned, adding that the literature indicates that 20 to 30 pregnancies have resulted from ovarian cryopreservation.
Oktay noted that oncologists are often concerned that ovarian stimulation and oocyte retrieval, whether followed by egg cryopreservation or in vitro fertilization (IVF) and embryo freezing, increases estrogen levels, which is especially problematic for women with breast and gynecologic malignancies. However, as the new guidelines state, studies indicate that using letrozole can stimulate the ovaries while shutting down estrogen production, making it a safer alternative to other stimulation regimens.
Additionally, the timing of stimulation is no longer tied to a woman's menstrual cycle “in most cases,” according to the new guidelines. Oncologists and hematologists, along with fertility specialists, can generally map out embryo or egg freezing in about two weeks, he said.
“Women generally undergo 10 days of fertility drug treatment, with egg collection occurring a couple of days later. We used to have to wait to start this process until after menstruation began, but new studies indicate we can start anytime during the cycle,” he said, citing one of his own papers: Fertil Steril 2011;95:2125.e9-11.
While the time it takes to collect eggs may be a concern to patients, from an oncologic perspective, it often takes two to three weeks to get an individual's cancer care organized, Loren noted. This “so-called delay” in treatment is normal, and a fertility preservation referral isn't going to prolong the waiting period. Still, patients with cancer need to be referred to fertility specialists as soon as a diagnosis is made.
Oncologists and other members of the health care team should not wait for people of childbearing age to bring up the topic of fertility preservation, Waggoner said.
Moreover, Munster added, “if fertility preservation is feasible, then the health care team needs to encourage patients to pursue it. Studies suggest that even patients who initially think preserving fertility is not important may come to regret [not having the option] later.”
GnRH Agonists Not Effective
New data are also making it increasingly clear that hormonal suppression of the ovaries is not a viable method for preserving fertility, Oktay said, and the new guidelines discourage its use.
Since the 2006 guidelines were published, several randomized studies have became available, including one by Munster (JCO 2012;30:533-538), evaluating the use of GnRHa in recovering menses and preserving fertility. At least two of the newer studies with longer follow-up and more contemporary chemotherapy do not show a benefit, she said, adding that the resumption of menses does not guarantee fertility.
More data are now also available indicating that BRCA carriers experience menopause earlier and have lower ovarian reserve, and their oocytes may also be more sensitive to the effects of chemotherapy, Oktay said.
“Consequently, we need to be more vigilant for women with BRCA mutations.” Additionally, if they decide to freeze their embryos, obtaining a preimplantation screening for BRCA mutations is possible to help prevent passing on the mutated gene to their offspring.
Male Guidelines and Prepubertal Approaches Unchanged
Information for male fertility preservation has not changed with the updated guidelines. However, while sperm banking is extremely easy, the practice is not frequently mentioned to men, Loren noted. “There's no reason not to mention it. Even if money is a concern, some [nonprofit health] organizations can help defray the cost.”
Low sperm counts are common with malignancy, and not just with testicular cancer, she continued. However, even if sperm counts are low, men shouldn't be dissuaded from banking, because using intracytoplasmic sperm injection for IVF is an option.
Prepubertal boys have the investigational option of testicular tissue freezing, which hasn't changed since the 2006 guidelines, Oktay noted. Ovarian tissue freezing is the only option available to prepubertal girls. No attempts have been made to restore the tissue to achieve a pregnancy in these patients because they are still too young, he said.
Barriers: Health Disparities and Access
In addition to the latest available data, the guidelines also address health care disparities that make access to fertility preservation difficult for some patients, noted Brian M. Slomovitz, MD, Director of Research for the Carol G. Simon Cancer Center and Associate Director of the Women's Cancer Center at Atlantic Health System's Morristown and Overlook Medical Centers in New Jersey. One topic that was glossed over, however, is that fertility treatment is often not covered by insurance.
Women and men with cancer and of childbearing age should undergo reproductive and endocrinology assessments, something that insurance may not pay for, he said. “All cancer patients should have the opportunity to meet with a reproductive specialist as long as this does not limit optimal cancer treatment.”
EDWARD ILLIONS, MD
Unfortunately, though, said Waggoner, “not every person who deserves these services will be able to get them. We need to try and aid patients who are poor or who have poor insurance or who live far from centers that can coordinate fertility preservation.”
The oncology team needs to serve as an advocate for patients and help them accomplish their childbearing goals,” he said. As the guidelines note, funding is often available through nonprofit health organizations such as the Livestrong Foundation.
Oktay and Loren both said that they hope that the updated guidelines encourage insurance companies to cover fertility preservation such as oocyte cryopreservation. “They have no problem covering breast reconstruction or wigs if people are undergoing chemotherapy,” Loren said. “Infertility is a preventable side effect of chemotherapy but is not covered in many circumstances. While there's definitely been progress with insurance companies, it could be addressed better.”
Oktay added that he hopes that new studies, such as his new individual patient data meta-analysis (Fertil Steril 2013;99:1496-5502) that indicates that frozen eggs result in pregnancy success rates similar to those of using unfrozen eggs and provides age-specific success rates, will encourage insurance companies to cover this procedure.