Oncologists should keep oncofertility ‘top of mind’ at diagnosis
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As the number of young cancer survivors continues to increase, so do the myriad of survivorship issues throughout their life span, including reproductive health concerns.
More than 10,000 reproductive-age women are diagnosed with gynecologic cancers each year in the United States, and several studies have shown that fertility preservation improves these patients’ ability to cope with their diagnosis and their quality of life in survivorship.
However, oncofertility may not always be “top of mind” among oncologists at the time of a new cancer diagnosis, Kirsten A. Jorgensen, MD, a fellow in the department of gynecologic oncology at The University of Texas MD Anderson Cancer Center, told Healio | HemOnc Today.
“We don’t know exactly what discussions are happening outside of anecdotes of our own experience,” Jorgensen said. “One study, published in 2009 in Journal of Clinical Oncology, demonstrated that only 47% of oncologists reported that they always or often refer patients to a fertility specialist when diagnosed with cancer. But that doesn’t tell us the full picture because it’s hard to know of all the patients who are diagnosed, how many want a referral, who desires this service and is not getting it, or whether is it us, the oncologists, who are not offering it.”
As oncologists focus on treating cancer with the goal of cure, they should also be mindful of survivorship needs, including fertility concerns, Matteo Lambertini, MD, PhD, assistant professor and consultant medical oncologist at the IRCCS Ospedale Policlinico San Martino at University of Genova in Italy, told Healio | HemOnc Today.
“Oncofertility needs of our patients should be addressed at the time of diagnosis, because some of the fertility preservation procedures can only be done before starting cancer treatment. We need to focus more on this from the time of the first medical consultation,” Lambertini said.
Such conversations should be happening with all patients of reproductive age, Lambertini continued.
“For example, discussions should explain the risks for developing premature ovarian insufficiencies from the side effects of the cancer treatments we are proposing,” he said. “We need to explain the risks and also offer strategies that are available to reduce complication risks.”
Healio | HemOnc Today spoke with experts about the effect of cancer treatments on fertility, ongoing research in this space and efforts to help clinicians broach the topic with their patients.
Pregnancy after breast cancer
Few data exist to evaluate the effect of cancer treatments on fertility for many cancer types, with the exception of breast cancer.
Breast cancer is the most common malignancy among women of reproductive age, accounting for approximately 30% of new cancer diagnoses worldwide among those aged younger than 40 years.
Advances in treatment have led to reductions in breast cancer mortality and increased emphasis on survivorship and potential long-term toxicities associated with therapy. Moreover, as age of first pregnancy rises, an increasing percentage of women are diagnosed with breast cancer prior to having children.
Lambertini and colleagues sought to assess chances of pregnancy after breast cancer, as well as reproductive and disease outcomes, among women who completed breast cancer treatment.
The systematic review and meta-analysis included 39 studies that enrolled a combined 8.26 million women, 114,573 of whom had breast cancer and 57,739 of whom had malignancies other than breast cancer. Approximately 6.5% of those with breast cancer (n = 7,505) became pregnant after diagnosis.
Results showed pregnancy after breast cancer did not have a negative effect on maternal outcomes regardless of tumor characteristics, BRCA status, type of prior treatment or timing of pregnancy. In addition, women who became pregnant after breast cancer achieved longer OS (HR = 0.56; 95% CI, 0.46-0.67) and DFS (HR = 0.73; 95% CI, 0.56-0.94) than women who did not have a subsequent pregnancy.
Lambertini and colleagues are now conducting research focused on how to discuss oncofertility with patients with hereditary cancer syndromes, such as BRCA-mutated breast cancer.
“In these cases, some data suggest there may be differences between patients with vs. without BRCA mutations or without hereditary cancer syndrome, but we still have limited data to perform good counseling for these patients,” Lambertini said. “The good news is that there are many ongoing efforts in this area, one of which is a large study that has included almost 5,000 breast cancer cases among women at a young age with a BRCA mutation, which will probably be presented or published by the end of this year.”
Options underutilized
Options for women who wish to preserve fertility after diagnosis of breast or gynecologic cancers include assisted reproductive technology (ART) — medical treatments or procedures that allow for oocyte or embryo freezing and later transfers — and fertility-sparing oncology care — surgical or medical interventions that retain the uterus and at least one ovary for women with gynecologic cancers.
However, these beneficial approaches appear to be underutilized, particularly among certain groups of women, a study by Jorgensen and colleagues showed.
The researchers evaluated rates of ART and fertility-sparing oncology care among 44,529 women aged 18 to 45 years in the California Cancer Registry database who had been diagnosed with stage I to stage III breast cancer, stage IA or stage IC ovarian cancer, stage IA or stage IB cervical cancer, or stage IA or stage IB endometrial cancer between 2004 and 2015.
Results showed that, overall, only 236 women (0.5%) utilized ART. Among those with a history of breast cancer, Black (OR = 0.32; 95% CI, 0.14-0.73) and Hispanic women (OR = 0.3; 95% CI, 0.19-0.49) received ART less frequently than non-Hispanic white women. Hispanic women with a history of cervical cancer also received ART less frequently than their white counterparts (OR = 0.33; 95% CI, 0.11-0.98).
Moreover, women with a history of breast cancer used ART less frequently if they lived in rural vs. urban areas (OR = 0.13; 95% CI, 0.04-0.39), as did recipients of Medicaid vs. private insurance (OR = 0.28; 95% CI, 0.14-0.56).
Fewer than one-quarter of women with a gynecologic malignancy (22.5%) received fertility-sparing oncology care, with white women and those who resided in rural areas less likely to receive such care.
“We found significant variations with respect to the populations of patients who actually receive fertility preservation treatments, such as egg or embryo freezing, or who receive fertility-sparing surgery,” Jorgensen told Healio | HemOnc Today. “We did see that these treatments were delivered mostly to younger people, which makes sense from a reproductive standpoint, but they were also more likely to be delivered to white individuals, with regard to ART, and to those with more resources such as private insurance or higher income.
“We unfortunately don’t know the full picture about what oncofertility discussions are happening, but we hope that the research we have conducted in conjunction with others will help prompt oncologists to have these discussions [with patients] and then prompt future prospective studies to understand more about the reality of where we are in this space and where we can get in the future,” she added.
Addressing safety concerns
Despite evidence in favor of fertility preservation for certain populations of patients with cancer, concerns remain regarding its safety after cancer diagnosis and treatment.
In a Swedish study published in JAMA Oncology last year, Marklund and colleagues examined the risk for disease-specific mortality and relapse among 1,275 women with breast cancer (mean age at diagnosis, 32.9 years) who underwent fertility preservation (n = 425) with or without hormonal stimulation compared with women who did not undergo fertility preservation (n = 850) at the time of breast cancer diagnosis between Jan. 1, 1994, and June 30, 2017.
Results showed similar disease-specific mortality among women who underwent hormonal fertility preservation (adjusted HR [aHR] = 0.59; 95% CI, 0.32-1.09) and those who underwent nonhormonal fertility preservation (aHR = 0.51; 95% CI, 0.2-1.29) compared with those who did not undergo fertility preservation.
Researchers reported 5-year breast cancer-specific survival rates of 96% among women who underwent hormonal fertility preservation, 93% among those who underwent nonhormonal fertility preservation and 90% among women who did not undergo fertility preservation, with corresponding 10-year rates of 88%, 90% and 81%.
In a separate study, Elizabeth S. Ginsburg, MD, professor at Harvard Medical School and fellowship director of the reproductive endocrinology and infertility program at Brigham and Women’s Hospital, and colleagues found fertility preservation after breast cancer diagnosis led to short delays in time to treatment, but those delays did not negatively impact survival outcomes.
The results, published in Cancer in 2021, showed women who underwent fertility preservation experienced longer times to first treatment (37 days vs. 31 days; aHR = 0.74; 95% CI, 0.56-0.99), neoadjuvant chemotherapy (36 days vs. 26 days; aHR = 0.41; 95% CI, 0.24-0.68) and from surgery to adjuvant therapy (41 days vs. 33 days; aHR = 0.58; 95% CI, 0.38-0.9) than those who did not undergo fertility preservation.
Yet, the groups had comparable adjusted rates of invasive DFS at 3 years (85.4% vs. 79.4%) and 5 years (73.7% vs. 67.1%). Moreover, researchers observed no differences between the fertility preservation and nonpreservation groups in rates of 3-year OS (95.5% vs. 93.5%) or 5-year OS (84.2% vs. 81.4%).
“Fertility is of particular concern among young breast cancer survivors, prompting a growing need to understand the implications of completing a fertility preservation cycle prior to initiation of cancer treatment,” Anna C. Vanderhoff, MD, researcher in the department of obstetrics, gynecology and reproductive biology at Brigham and Women’s Hospital, and colleagues, told Healio | HemOnc Today in a previous interview. “The goal of this research was to be able to provide clinicians and patients with evidence-based answers regarding the impact of fertility preservation on timing of treatment and breast cancer outcomes. We will continue research in this area to provide high-quality data when discussing the pros and cons of fertility preservation with our patients. We hope to examine the impact of fertility preservation on specific breast cancer subtypes and other forms of malignancy.”
Other cancer types
Cancer centers are now collaborating to fill the knowledge gaps regarding fertility among patients with other types of malignancies, according to Ginsburg.
“At Brigham and Women’s Hospital, we are working to establish a multicenter database repository of sorts to look at fertility preservation outcomes in patients with various cancer types,” Ginsburg told Healio | HemOnc Today. “There is so much published on breast cancer, but there is relatively little published on other less common cancers, such as brain tumors, gastrointestinal cancers and sarcomas. That is why we got together with other academic centers. We have most of the data-sharing agreements and should be able to start the project within the next few months.”
Finding out more about patients who present with less common tumor types is important particularly because such data can inform counseling, she added.
“There really is not much information available about whether the cancer itself or the cancer treatments impact future fertility,” Ginsburg said. “Some treatments are sterilizing, such as colon cancer treatment, which involves radiation and chemotherapy that is pretty much 100% sterilizing for women.”
Additional next steps in research include identifying what percentage of women who freeze eggs or embryos come back to use them, Ginsburg continued.
“At Dana-Farber Cancer Institute, there is a young person’s cancer program that includes a nurse navigator whose sole job is to identify patients in their reproductive years who are facing cancer treatments that could impact their fertility and talking with them about it,” she said. “Financial resources need to be put into this because there is no question that early consults consist of a lot of information, and it’s very hard for the oncologist and patient to understand the potential impact on infertility in the course of an hour-and-a-half consult.”
Ginsburg recommended providing patients with written information on fertility issues that they can review after the consult.
“Some oncologists acknowledge that they don’t get to discuss the potential impact of the patient’s future treatment on their fertility, which means we really need something in writing,” she said. “We still see patients who have not realized, even if it has been discussed with them, the impact of a treatment on their fertility until they sign their consent forms. Some patients may have had it explained to them in the past, but it’s not until they see it in writing that they actually absorb it. Writing helps, and hearing something more than once is also helpful.”
Ongoing work needed
Experts with whom Healio | HemOnc Today spoke agreed that continued work is needed to bring discussions about fertility to the forefront of oncology care.
“As oncologists, we need to do better in addressing the survivorship needs of our patients,” Lambertini said. “When we discuss cancer treatment, we should also discuss with patients not only their prognosis and the benefit of the treatment we are offering, but also the short-term and particularly long-term consequences of treatment. We also need to try to prevent — whenever possible or overcome when prevention isn’t possible — these types of toxicities because we want our patients to have a life after cancer as similar as possible to the life before their cancer.”
Jorgensen agreed and said there are many reasons to remain invested in patients’ quality of life and who they are as a person outside of their cancer diagnosis.
“The work in this area is critically important for young patients with cancer, and we hope to shine more light on the niche area of oncofertility and provide actual data to help patients and their health care providers make decisions regarding the oncologic safety of fertility-sparing or fertility-preserving procedures and their future potential impact on successful pregnancies,” Jorgensen said. “We want our research in this area to also help medical providers and patient advocacy groups make changes on a policy level to allow for more people to receive expanded services in this area.”
Ginsburg said early referral to a reproductive specialist is key.
“A reproductive endocrinologist will never be upset about counseling a patient who maybe later decides against fertility preservation, but it’s really sad when we see a patient posttreatment who never had the opportunity to talk to anybody beforehand,” Ginsburg said. “The take-home should be early referral. If in doubt, refer.”
Oncologists can review a list of reproductive programs online at the Society for Assisted Reproductive Technology website, www.sart.org, Ginsburg added. “Even if an oncologist doesn’t know a specific reproductive endocrinologist, they’ll be able to find a clinic in their area,” she said.
Jorgensen said the conversation should start with the oncologist.
“Oncologists should establish relationships with reproductive specialists in our respective areas in order to streamline referrals and assist patients. Doing so can go a long way in helping to make this a resource that is more accessible to more people,” she said. “As oncologists, we must provide opportunities for our patients so that, in the future, we see differences in outcomes when it comes to who is receiving oncofertility services. We must keep oncofertility at the forefront of our minds when it comes to our reproductive-age patients.”
References:
- Blondeaux E, et al. Abstract GS3-09. Presented at San Antonio Breast Cancer Symposium (virtual meeting); Dec. 8-11, 2020.
- Greer AC, et al. Cancer. 2021;doi:10.1002/cncr.33601.
- Jorgensen K, et al. Abstract 94. Presented at: Society of Gynecologic Oncology 2022 Annual Meeting on Women’s Cancer (hybrid meeting); March 18-21, 2022; Phoenix.
- Quinn GP, et al. J Clin Oncol. 2009;doi:10.1200/JCO.2009.23.0250.
For more information:
Elizabeth S. Ginsburg, MD, can be reached at eginsburg@bwh.harvard.edu.
Kirstin A. Jorgensen, MD, can be reached at kajorgensen@mdanderson.org.
Matteo Lambertini, MD, PhD, can be reached at matteo.lambertini@hsanmartino.it.
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