Advanced diagnostic tools and innovative treatment measures in cancer have increased cancer survival rates in the United States. Efforts by the various stakeholders in the drug development process—research scientists, the pharmaceutical industry, the FDA—resulted in the approval of 6 new anticancer agents over a 1-year period ending July 31, 2014, according to the 2014 Progress Report by the American Association for Cancer Research. Additionally, 5 previously approved agents were endorsed for alternate indications.1
Along with increased incidence, there has been a significant increase in the number of cancer survivors. While the United States had an estimated 3 million survivors in 1971, that estimate is expected to reach about 14.5 million in 2014, with nearly 380,000 having been diagnosed as children or adolescents.1 One issue that plagues cancer survivors is quality of life, which could stem from either emotional or physical problems, or a combination of the two. Infertility is a major concern: irradiation of the testes or a regimen that includes chemotherapy, especially alkylating agents, can reduce fertility.
Cancer Treatment and Fertility
Chemotherapy drugs and radiation, commonly used regimens in cancer patients, es-pecially when used in the pelvic region, can cause genetic changes in the sperm and oocytes. These treatment regimens can cause damage to the hypothalamicpituitary-gonadal axis and can also damage the organs of the reproductive tract. Although unpredictable, the possibility of infertility following treatment cannot be ruled out. Some of the factors that could influence fertility after cancer treatment include: age, type of treatment, dose and type of chemotherapy, and the amount
and site of radiation.2,3
“However, not all cancer regimens impact fertility, and so it is important to stratify risk for the patients,” Teresa Woodruff, PhD, director, Women’s Health Research Institute, and chief, Division of
Obstetrics and Gynecology-Fertility Preservation, at Northwestern University in Chicago, told Evidence-Based Oncology. Researchers at the St. Jude Children’s Research Hospital, in Memphis, Tennessee, are doing just that.
Childhood Cancer Survivor Study
In an effort to understand the long-term effects of cancer and its treatments, as well as to provide an opportunity to better educate survivors, the St. Jude Children’s Research Hospital initiated the Childhood Cancer Survivor Study (CCSS). CCSS includes all participants in the Long Term Follow Up Study, which is jointly funded by the National Cancer Institute and ALSAC (a St. Jude fund-raising organization). Included in this retrospective study were 20,346 childhood cancer survivors (diagnosed between 1970 and 1986) and 4000 sibling survivors as controls.3,4 Due to the
revolutionary changes in the treatment of pediatric cancers, the Long Term Follow Up Study is in the process of recruiting 15,000 survivors of childhood cancer diagnosed between 1987 and 1999, with 4000 sibling controls.4
The findings of the various retrospective studies conducted among those diagnosed between 1970 and 1986 are not encouraging. The studies identified a drop in pregnancy rates and an increased risk of infertility among female survivors compared with their female siblings, while male survivors were less likely to father children compared with their male siblings (see Table).5-8
St. Jude Lifetime Cohort Study
A study published recently in Lancet Oncology reported the results of a semen analysis of participants in the St. Jude Lifetime Cohort Study, who were diagnosed and treated for cancer between 1970 and 2002.9
The participants—214 qualified adult male survivors—were treated with an alkylating agent without radiation. These childhood cancer survivors had a median age of 7.7 years at diagnosis, 29 years at assessment, and 21 years since diagnosis. Drug exposure was estimated as the cyclophosphamide equivalent dose (CED), which is a unit for quantifying alkylating agent exposure independent of the study population.10 The outcome: a dose greater than 4000 mg/m2 of the alkylating agent was associated with impaired spermatogenesis, which led the authors to recommend pretreatment patient counselling and fertility preservation services.
Fertility Impairment in Young Adult Cancer Patients
In female cancer patients, treatments such as total body irradiation, or ovarian damage due to chemotherapy (highdose chemotherapy, alkylating agents) or due to radiation, can result in infertility. Younger women, and those receiving low doses of chemotherapy radiation, may recover their menstrual cycle earlier. However, the woman’s age definitely has a significant impact on this recovery—the younger the better.2 Similarly, in men, removal of the testicles or treatment with a high dose of radiation or alkylating chemotherapy could result in infertility.2
There are several standard and a few experimental techniques for fertility preservation. Some of the standard methods in women include:
1. Embryo banking. This may entail the use of fertility drugs to improve egg quality, surgical harvesting of eggs, in vitro fertilization, and banking the embryos. This procedure can cost between $5000 and $8000 and may not be covered by standard health plans,11 although some patients may have coverage if they were covered by a voluntary cancer plan before they were diagnosed.
2. Pelvic shielding during radiation therapy.
3. Ovarian transportation. A surgeon moves the ovaries to a different part of the patient’s body, away from the region receiving radiation.
4. Removal of the cervix, but not the uterus, in those with early-stage cancer.2,11
Some of the experimental methods in women include:
1. Egg banking. Unfertilized eggs are frozen, which may require prior treatment with fertility drugs. This technique has resulted in fewer than 200 live births worldwide.
2. Ovarian tissue banking. The surgeon removes small pieces of the ovary and stores the frozen tissue, to be replanted following cancer treatment.
3. Medical treatment to shut down the ovaries during chemotherapy—a temporary menopause.2,11
In men, the procedure is simpler, cheaper, and proved effective: collecting and freezing the sperm sample. Sperm quality can be evaluated under a microscope and only the healthy sperms isolated to fertilize the donor egg. Although not covered by insurance, the cost for storing the specimen for 5 years is about $500.2
Support for Fertility Preservation
Various organizations are raising a strong voice to support this aspect of survivorship care, including the LIVESTRONG foundation12 and the National Institutes of Health—funded Oncofertility Consortium.13 The programs strive to keep the patients informed about the fertility risks associated with cancer regimens and educate them on the available options to preserve their fertility. The Oncofertility Consortium, for example, is a multidisciplinary team of physicians spanning more than 50 national sites, with its core at Northwestern University.14 The Consortium offers a digital
resource, iSaveFertility, a mobile app that provides patients, parents of young children, and physicians information on protecting the reproductive health of cancer patients and survivors.15
Northwestern’s Woodruff told EBO that each patient is assigned to an oncofertility patient navigator who provides tailored or personalized information to the patient, pertinent to their needs.
When queried on the receptiveness of parents of young patients to the idea of fertility preservation, Woodruff replied that in her experience, most parents have been quite resilient, because they want their child to survive with the same fullness of life and the expectations as any of their peers. “They intervene on their child’s behalf—these parents have to make a number of hard choices when it comes to some of the harshest treatment decisions. Not everyone will opt for the treatment, but at least they’ll make an informed decision,” said Woodruff.
According to Woodruff, there’s increasing awareness among patients due to concerted efforts by medical oncologists and fertility specialists who have opened up dialogues with their patients on preserving fertility prior to initiating treatment. “While there were zero referrals back in 2005, 50% to 80% of cancer patients today are referred to fertility preservation treatment,” she said. Woodruff believes primary care physicians, oncologists, and oncology nurses are the gateway to all referrals, and she also credited increasing social awareness as another reason why patients seek fertility preservation.
An important question in discussing fertility preservation with cancer patients is insurance coverage. There seems to be a great deal of disparity when it comes to the discussion on fertility preservation between an oncologist and a patient, and oncologists may or may not introduce the option to the patients or their family. The high cost of treatment, coupled with the lack of coverage, seems to be the primary reasons why they don’t initiate a dialogue with their patients on the topic.16 This could have a tremendous impact on patients from lower socioeconomic backgrounds, and this is where patient navigators could play an extremely important role—raising awareness among patients about their possible options.
Oncofertility patient navigators can educate the patient and his or her family on fertility preservation procedures as well as associated costs. A well-informed navigator could keep the patient informed on reimbursement information in addition to helping patients navigate the necessary paperwork with their insurance company. Patient navigators could also direct patients to organizations like the LIVESTRONG foundation that assist with easing some of the financial burden.17
In addition to facing the prognosis on their cancer and fertility, the patient might be overwhelmed by the fact that fertility preservation might add another financial burden due to lack of coverage. A paper published in 2010 in the Journal of Law, Medicine and Ethics recommended expanding the definition of infertility to include those who would be rendered infertile following cancer treatment. The authors argue that the expansion would ensure that cancer patients can receive fertility preservation technology prior to initiating their treatment. Disputing the existing definition of infertility as the “reactive” behavior of medicine, the authors suggest that medicine should also be considered “proactive”—preventing conditions from existing in the future, which they equate with patients being prescribed a blood pressure medication to prevent a heart attack.18
Policy Initiatives to Turn the Tide
Efforts from various quarters are ongoing to draw attention to this important and quite neglected aspect of cancer survivorship care.
A bill submitted to the California State Assembly in February 2013, AB-912, would require a healthcare service plan and a health insurer to cover, on a large-group basis, fertility preservation services in patients who are at risk of infertility following treatment for certain disease conditions, including cancer.19 The bill was vetoed by Governor Edmund G. Brown Jr, who cited the need to consider the widespread impact of the mandates implemented by the Affordable Care Act before making such coverage changes.
The Michigan delegation of the American Medical Association (AMA) introduced Resolution 114, calling for association wide support of insurance coverage for fertility preservation in cancer patients, and also supporting lobbying for federal legislation on payment for oncofertility treatment.20 This resolution was adopted as a new policy by the AMA in June 2013.21
At the federal level, the Family Act S 881/HR 1851, introduced in the Senate and House of Representatives in May 2013, is meant to make the treatment affordable. The act, if passed, would provide tax credits for eligible taxpayers to cover 50% of the cost of in vitro fertilization and fertility preservation.20 The bill must pass both the House and the Senate before the end of the current session of Congress in December 2014 and be signed by President Obama to become a law.22References
1. American Association for Cancer Research. AACR cancer progress report, 2014. http://www.cancerprogressreport-digital.org/cancerprogressreport/2013#pg1. Accessed September 22, 2014.
2. Preserving fertility before treatment. http://www.mdanderson.org/patient-and-cancer-information/cancer-information/cancer-topics/detection-and-diagnosis/preserving-fertility/index.html. MD Anderson Cancer Center website. Accessed September 18, 2014.
3. Cardonick EH. Overview of infertility and pregnancy outcome in cancer survivors. UpToDate website. http://www.uptodate.com/contents/overview-of-infertility-and-pregnancy-outcome-in-cancer-survivors#H2. Reviewed June 9, 2014. Accessed September 23, 2014.
4. The Childhood Cancer Survivor Study. St. Jude Children’s Research Hospital website. https://ccss.stjude.org/about/learn-more. Accessed September 23, 2014.
5. Green DM, Kawashima T, Stovall M, et al. Fertility of female survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol. 2009;27(16):2677-2685.
6. Barton SE, Najita JS, Ginsburg ES, et al. Infertility, infertility treatment, and achievement of pregnancy in female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol. 2013;14(9):873-881.
7. Green DM, Nolan VG, Kawashima T, et al. Decreased fertility among female childhood cancer survivors who received 22-27 Gy hypothalamic/pituitary irradiation: a report from the Childhood Cancer Survivor Study. Fertil Steril. 2011;95(6):1922-1927.
8. Green DM, Kawashima T, Stovall M, et al. Fertility of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2010;28(2):332-339.
9. Green DM, Liu W, Kutteh WH, et al. Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study [published online September 17, 2014]. Lancet Oncol. 2014. doi:10.1016/S1470-2045(14)70408-5.
10. Green DM, Nolan VG, Goodman PJ, et al. The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer. 2014;61(1):53-67.
11. Women and cancer: preserving fertility. http://www.savemyfertility.org/fact-sheets/preserving-fertility. Savemyfertility website. Accessed September 25, 2014.
12. LIVESTRONG fertility. http://www.livestrong.org/we-can-help/fertility-services/. LIVESTRONG Foundation website. Accessed September 23, 2014.
13. http://www.myoncofertility.org/. MyOncofertility.org website. Accessed September 23, 2014.
14. Core centers. http://oncofertility.northwestern.edu/about-us/primary-centers. The Oncofertility Consortium website. Accessed September 24, 2014.
15. http://www.savemyfertility.org/. SaveMyFertility.org website. Accessed September 24, 2014.
16. Campo-Engelstein, L. Insurance coverage for oncofertility: concerns about socioeconomic disparities. http://www.amc.edu/BioethicsBlog/post.cfm/insurance-coverage-for-oncofertility-concerns-about-socioeconomic-disparities. Albany Medical College website. Published June 16, 2014. Accessed September 24, 2014.
17. Smith K, Efymow B, Gracia C. Patient navigation and coordination of care for the oncofertility patient: a practical guide. In: Gracia C, Woodruff TK, eds. Oncofertility Medical Practice: Clinical Issues and Implementation. New York, NY: Springer Science+Business Media; 2012:175-185.
18. Basco D, Campo-Engelstein L, Rodriguez S. Insuring against infertility: expanding state infertility mandates to include fertility preservation technology for cancer patients. J Law Med Ethics. 2010;38(4):832-839.
19. AB-912 Health care coverage: fertility preservation. http://leginfo.legislature.ca.gov/faces/billHistoryClient.xhtml. California Legislative Information website. Accessed September 24, 2014.
20. Oncofertility policy initiatives: affording fertility preservation. http://oncofertility.northwestern.edu/policy. The Oncofertility Consortium website. Accessed September 25, 2014.
21. AMA adopts new policies on first day of voting at annual meeting [press release]. Chicago, IL: American Medical Association; June 17, 2013. http://www.ama-assn.org/ama/pub/news/news/2013/2013-06-17-new-ama-policies-annual-meeting.page.
22. Family Act Bill status, S 881/HR 1851. http://www.resolve.org/get-involved/the-center-for-infertility-justice/federal-legislation/family-act-of-2011-bill-status.html. Resolve website. Updated September 2, 2014. Accessed September 25, 2014.