Each year in the United States, more than 60,000 young adults, 20 to 39 years of age, are diagnosed with cancer. The most common diagnoses requiring treatment that may impair fertility are lymphoma; leukemia; sarcoma; and cancers of the breast, testis, cervix, ovary, colon, rectum, brain, and spinal cord.
Because many of these young patients will not have started or completed their families at the time of diagnosis, they often have reproductive concerns. Recognizing the significance of fertility as both a health and quality of life issue, a number of professional organizations have developed guidelines highlighting the need for clinicians working in all disciplines of oncology to address fertility with their at-risk patients—informing them of their risk of infertility, describing options for fertility preservation, and referring interested patients to appropriate reproductive specialists.[3-6] Not all patients will need, want, or be able to pursue fertility preservation before undergoing treatment for their cancer, but most want the opportunity to talk with health professionals about their options. This article will outline key information needed and practical ways that clinicians can integrate fertility preservation discussions and guidelines into their day-to-day practice.
Potential Reproductive Effects of Cancer Treatment
One of the most challenging aspects of discussing fertility with young newly diagnosed cancer patients is the impossibility of predicting with certainty a patient’s individual risk of infertility. Drug regimens are constantly evolving, and there are limited data (or no data) available on the fertility effects of most of the new targeted agents and immunotherapies. With the movement toward personalized medicine, the difficulty of predicting risk will only increase.
In general, alkylating agents pose the highest risk of infertility, and platinum analogs, anthracyclines, and taxanes pose an intermediate risk, with the degree of risk affected by the cumulative drug dose.[7-9] Specific treatment regimens are generally classified as being of high (> 80%), moderate (20% to 80%), or low (< 20%) risk of fertility impairment, but these are imprecise measures by which to base decisions about fertility preservation.
In men, chemotherapy and exposure of the testes to radiation can impair sperm production by destroying spermatogonial stem cells. Recovery of spermatogenesis after treatment depends on the survival of these cells and their ability to replicate and mature into sperm; sperm production generally returns within 1 to 3 years but can be delayed longer depending on the specific agents and doses used in cancer treatment. Men may experience complete recovery, with normal sperm counts; partial recovery, with low sperm counts; or no recovery, with absence of sperm in the semen (azoospermia).
Pelvic irradiation or surgery may damage male reproductive system blood vessels, nerves, and collecting ducts, which can result in erectile and ejaculatory dysfunction. In many such cases, men may be producing sperm but cannot deliver it naturally to a female partner through intercourse. Finally, cranial irradiation or surgery that damages the pituitary gland may cause hormonal alterations that impair spermatogenesis.
In women, oocytes can be destroyed by both chemotherapy and exposure of the ovaries to radiation.[9,10] Women are born with a finite number of oocytes, which are lost continuously through apoptosis. Maintenance of fertility and ovarian function depends on the number of oocytes remaining after treatment (the ovarian reserve); therefore, older women, who have fewer oocytes before undergoing treatment, are at greater risk of infertility than younger women. Some women go into menopause immediately; others may resume menses after treatment but remain at risk for developing infertility and menopause at a young age.
Radiation therapy to the pelvis with exposure of the uterus causes atrophy, fibrosis, and vascular changes, with subsequent damage to the endometrium and myometrium. This may hinder embryo implantation and the establishment of pregnancy, and if pregnancy is established, uterine exposure to radiation confers a risk of miscarriage and preterm birth.
Cranial irradiation or surgery that damages the pituitary gland may result in hormonal alterations that impair oocyte maturation and ovulation.
Options to Preserve Fertility Before Treatment
Clinicians should initiate discussions about fertility preservation as early as possible in the treatment planning process. This will ensure that interested patients are identified and referred to appropriate reproductive specialists with enough time to pursue fertility preservation without delaying their cancer treatment. Tables 1 and 2 outline the options available for men and women to preserve fertility before treatment begins.
1. American Cancer Society. What are the key statistics for cancers in young adults? 2015. Updated June 10, 2015. https://www.cancer.org/cancer/cancer-in-young-adults/key-statistics.html. Accessed June 10, 2017.
2. American Cancer Society. Cancers that develop in young adults. 2015. Updated June 10, 2015. https://www.cancer.org/cancer/cancer-in-young-adults/cancers-in-young-adults.html. Accessed June 10, 2017.
3. American Society for Reproductive Medicine. Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertil Steril. 2013;100:1214-23.
4. Coccia PF, Pappo AS, Altman J, et al. Adolescent and young adult oncology, version 2.2014. J Natl Compr Canc Netw. 2014;12:21-32.
5. Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31:2500-10.
6. Neuss MN, Gilmore TR, Belderson KM, et al. 2016 updated American Society of Clinical Oncology/Oncology Nursing Society chemotherapy administration safety standards, including standards for pediatric oncology. J Oncol Pract. 2016;12:1262-71.
7. Meistrich ML. Male gonadal toxicity. Pediatr Blood Cancer. 2009;53:261-6.
8. Trost L, Brannigan R. Fertility preservation in males. In: Gracia C, Woodruff TK, editors. Oncofertility medical practice: clinical issues and implementation. New York: Springer; 2012. pp. 27-50.
9. Ben-Aharon I, Shalgi R. What lies behind chemotherapy-induced ovarian toxicity? Reproduction. 2012;144:153-63.
10. Meirow D, Biederman H, Anderson RA, Wallace WH. Toxicity of chemotherapy and radiation on female reproduction. Clin Obstet Gynecol. 2010;53:727-39.
11. Teh WT, Stern C, Chander S, Hickey M. The impact of uterine radiation on subsequent fertility and pregnancy outcomes. Biomed Res Int. 2014;2014:482968.
12. LIVESTRONG Foundation. Family-building options for men. 2013. http://images.livestrong.org/pdfs/livestrong-fertility/LF_PreservationOptionsChart_Men.pdf. Accessed June 14, 2017.
13. LIVESTRONG Foundation. Family-building options for women. 2013. http://images.livestrong.org/pdfs/livestrong-fertility/LF_PreservationOptionsChart_Women.pdf. Accessed June 14, 2017.
14. Katz DJ, Kolon TF, Feldman DR, Mulhall JP. Fertility preservation strategies for male patients with cancer. Nat Rev Urol. 2013;10:463-72.
15. Kort JD, Eisenberg ML, Millheiser LS, Westphal LM. Fertility issues in cancer survivorship. CA Cancer J Clin. 2014;64:118-34.
16. Moss JL, Choi AW, Fitzgerald Keeter MK, Brannigan RE. Male adolescent fertility preservation. Fertil Steril. 2016;105:267-73.
17. Nangia AK, Krieg SA, Kim SS. Clinical guidelines for sperm cryopreservation in cancer patients. Fertil Steril. 2013;100:1203-9.
18. American Society for Reproductive Medicine. Mature oocyte cryopreservation: a guideline. Fertil Steril. 2013;99:37-43.
19. Cakmak H, Rosen MP. Ovarian stimulation in cancer patients. Fertil Steril. 2013;99:1476-84.
20. Rodriguez-Wallberg KA, Oktay K. Fertility preservation during cancer treatment: clinical guidelines. Cancer Manag Res. 2014;6:105-17.
21. Jensen AK, Macklon KT, Fedder J, et al. 86 successful births and 9 ongoing pregnancies worldwide in women transplanted with frozen-thawed ovarian tissue: focus on birth and perinatal outcome in 40 of these children. J Assist Reprod Genet. 2017;34:325-36.
22. Meirow D, Ra’anani H, Shapira M, et al. Transplantations of frozen-thawed ovarian tissue demonstrate high reproductive performance and the need to revise restrictive criteria. Fertil Steril. 2016;106:467-74.
23. Ghadjar P, Budach V, Kohler C. Modern radiation therapy and potential fertility preservation strategies in patients with cervical cancer undergoing chemoradiation. Radiat Oncol. 2015;10:50.
24. Blumenfeld Z, Zur H, Dann EJ. Gonadotropin-releasing hormone agonist cotreatment during chemotherapy may increase pregnancy rate in survivors. Oncologist. 2015;20:1283-9.
25. Del Mastro L, Ceppi M, Poggio F, et al. Gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in cancer women: systematic review and meta-analysis of randomized trials. Cancer Treat Rev. 2014;40:675-83.
26. Lambertini M, Cinquini M, Moschetti I, et al. Temporary ovarian suppression during chemotherapy to preserve ovarian function and fertility in breast cancer patients: a GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology. Eur J Cancer. 2017;71:25-33.