Incorporating fertility preservation into the care of young oncology patients

Incorporating Fertility Preservation Into the Careof Young Oncology Patients Amanda J. Redig, PhD1; Robert Brannigan, MD2; Steven J. Stryker, MD3,4; Teresa K. Woodruff, PhD4,5; and As the number of cancer survivors continues to increase, oncologists are faced with the challenge of providing cancer therapy to patients who may 1 day want to have children. Yet, gonadotoxic cancer treatments can compromise future fertility, either temporarily or permanently. There are established means of preserving fertility before cancer treat- ment; specifically, sperm cryopreservation for men and in vitro fertilization and embryo cryopreservation for women.
Several innovative techniques are being actively investigated, including oocyte and ovarian follicle cryopreservation, ovarian tissue transplantation, and in vitro follicle maturation, which may expand the number of fertility preservation choices for young cancer patients. Fertility preservation may also require some modification of cancer therapy; thus, patients’ wishes regarding future fertility and available fertility preservation alternatives should be discussed before initiation of therapy. This commentary provides an overview of the range of fertility preservation options currently available and under development, using case-based discussions to illustrate ways in which fertility preservation can be incorporated into oncology care. Cases involving breast cancer, testicular cancer, and rectal cancer are described to illustrate fertility issues experienced by male and female patients, as well as to provide examples of strategies for modifying surgical, medical, and radiation therapy to spare fertility. Current guidelines in oncology and reproductive medicine are also reviewed to underscore the importance of communicating fertility preservation options to young patients with cancer. Cancer 2011;117:4–10. V KEYWORDS: fertility, chemotherapy, radiation therapy, cryopreservation, breast cancer, testicular cancer, colorectalcancer.
Cancer continues to be a leading cause of mortality, yet new and effective therapies have led to an increase in the num-ber of cancer survivors. There are over 10 million cancer survivors in the United States alone.1 Whereas the incidence ofmany cancers increases with age, 1 in 168 Americans will be diagnosed with a malignancy between the ages of 15 and 30.2Greater success in treating cancer brings a new challenge for the oncologist treating younger patients: providing cancertreatment for patients who have a very real possibility of 1 day having children. This requires an expanded perspective onthe potential long-term consequences of the cancer itself as well as the impact of intense and often highly toxic therapy onpatients’ future fertility. To this end, a recent study found patient concerns about future fertility ranked second only toquestions about mortality.3 Ongoing research efforts have led to expanded fertility preservation options for both men and women diagnosed with cancer, and it is increasingly important for the care offered to younger oncology patients to include discussions aboutfamily planning and fertility preservation. As some approaches to fertility preservation may require modification in thetiming of a patient’s treatment and cannot be implemented once systemic therapy has begun, integration of fertility issuesinto initial discussions about cancer treatment is essential. Multidisciplinary cancer care requires close communicationbetween surgical oncologists, radiation oncologists, and medical oncologists during the development of a treatmentplan.4-6 This structured interaction should enable incorporation of fertility preservation into cancer management. Bybriefly reviewing the advances in fertility preservation for cancer patients and using case studies, this commentary willillustrate how fertility planning can be integrated into oncology practice to enhance the lives of cancer survivors.
Corresponding author: Jacqueline S. Jeruss, MD, PhD, Department of Surgery, Northwestern University Feinberg School of Medicine, 250 East Superior Street,Prentice, 4-420, Chicago, IL 60611; Fax: (312) 503-2555; 1Northwestern University Feinberg School of Medicine, Chicago, Illinois; 2Department of Urology, Northwestern University Feinberg School of Medicine, Chicago;3Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois; 4Robert H. Lurie Comprehensive Cancer Center, NorthwesternUniversity, Chicago, Illinois; 5Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois DOI: 10.1002/cncr.25398, Received: January 22, 2010; Accepted: March 19, 2010, Published online August 31, 2010 in Wiley Online Library( Fertility Preservation Cancer Patients/Redig et al Figure 1. Navigation of the oncofertility treatment path is illustrated. Questions about a young patient’s desire for future fertilitybegin with a cancer diagnosis. If a patient is not interested in fertility preservation, cancer therapy can proceed. However, if apatient is interested in attempting to preserve future fertility, the next steps involve both patient counseling and coordination ofcare. A fertility preservation plan can be tailored to an individual’s circumstances and reflect both established and experimental options. After a treatment plan incorporates both the need to treat a patient’s disease and their wishes regarding future fertility,the final step is initiation of cancer therapy.
complex decision. While IVF with embryo cryopreserva- Fertility preservation options can be divided into several tion remains the option most likely to succeed, ongoing categories (Fig. 1). First, germ line cells can be preserved research efforts in artificial reproductive therapy are exam- directly. In postpubertal male patients, this involves sperm ining approaches that would expand fertility preservation banking. For younger pubertal male patients, where col- options. Technologies are being used to remove ovarian lection of a semen sample may be more difficult, vibratory tissue, which contains immature oocytes, and cryopre- stimulation, electroejaculation, or surgical sperm extrac- serve strips of cortical tissue or individual follicles before tion can be attempted.7,8 Currently, no viable options are therapy.11,14-16 Cortical tissue strips can then be reim- in place for prepubertal boys, though this is an area of planted after cancer therapy has concluded, in an attempt active investigation. For female patients, the most to restore ovarian function. This approach has resulted in accepted therapy involves hormonal stimulation, oocyte 6 reported live births for patients who have completed retrieval, and either oocyte cryopreservation or in vitro their cancer treatment, with 5 additional births presented fertilization (IVF), followed by embryo cryopreservation at a recent meeting of the International Society of Fertility before initiating therapy.9-12 It is critical that the female Preservation.14,16-19 However, this technique remains patient have her baseline fertility assessed before any inter- experimental and may carry the risk of reintroduction of vention for fertility preservation, particularly for women cancer cells upon autotransplantation.15,16,20,21 Labora- over the age of 35, due to the natural reduction in ovarian tory efforts for in vitro maturation of cryopreserved reserve. At this point, over 500 live births have been immature follicles have shown promise in animal and achieved using cryopreserved oocytes from young women, human studies.22-25 Although not yet an option for yet this technique is still considered experimental.13 IVF, patients, the ability to cryopreserve immature follicles while often successful, necessitates that patients without within ovarian cortical material to mature them at a later partners choose a sperm donor, which can be a highly date would facilitate fertility preservation for the youngest female cancer patients not eligible to undergo assisted for patients diagnosed during their reproductive years.38,39 However, any change to standard therapy In addition to direct germ-line preservation, other requires discussion between patient and physician on a strategies can be discussed with younger cancer patients case-by-case basis. For example, in the setting of colorectal who desire children. Male patients who are unable to bank cancer, standard 5-FU therapy does not seem to have dele- sperm before cancer treatment may consider IVF using a terious effects on fertility while the use of newer adjuvant sperm donor. Similarly, for women who do not preserve agents such as oxaliplatin may introduce more fertility- embryos or oocytes before cancer treatment, but who main- threatening side effects.40 Furthermore, the incorporation tain a functional reproductive tract after therapy, IVF with of improved diagnostics may provide a more accurate donor eggs can be used to achieve pregnancy. For those assessment of patients who are likely to benefit from patients who cannot carry a pregnancy, use of a gestational chemotherapy. The recently developed Oncotype DX test carrier or adoption are also options that can be considered.
may help breast cancer patients and clinicians make deci-sions regarding postsurgery chemotherapy on the basis of tumor molecular markers and the likelihood of disease Modification of surgical protocols can also be part of inte- recurrence.41 Implementation of new diagnostic tools grating fertility preservation into cancer therapy. For may allow some younger patients to avoid gonadotoxic young women with gynecologic malignancies, standard therapy often involves aggressive surgical resection that Data suggest that in certain malignancies, including makes future pregnancies impossible. However, emerging testicular cancer and Hodgkin disease, compounds pro- data suggest that less aggressive resection can be used to duced by the tumor itself can be spermatotoxic before the successfully treat malignancy while still preserving fertil- initiation of therapy, resulting in chromosomal aneu- ity. Conservative management of endometrial carcinoma ploidy.42 In addition, chromosomal abnormalities in or ovarian carcinoma with subsequent fertility in young spermatocytes can be detected up to 24 months after patients has been reported, while ongoing studies are eval- chemotherapy.42 Fertility discussions with these patients uating the clinical efficacy of fertility-sparing conical exci- should include the possibility that cryopreserved sperm sions in women with cervical cancer.26-29 may not lead to a viable pregnancy. The role of preim- Radiation therapy is gonadotoxic in a dose-depend- plantation genetic diagnosis may also be discussed with ent manner and has been shown to damage developing sperm as well as decrease ovarian reserve.30-33 In the caseof gastrointestinal tumors, relative proximity to the repro- ductive tract is a concern, as radiation used to treat the Conversations about fertility preservation in cancer primary tumor may have deleterious secondary effects on patients are most effective when they occur before initia- future fertility.34 However, as with other treatment tion of treatment. Germ line tissue banking for both male modalities, recognition of this challenge before initiation and female patients optimally should take place before of gonadotoxic radiation can help preserve fertility in any cancer-related surgical resection of reproductive tissue some patients. Sperm cryopreservation can be offered to and before initiation of chemotherapy. This is particularly men, whereas surgical ovarian transposition out of the relevant for female patients, as the effects of chemotherapy radiation field and/or oocyte or embryo preservation are become more pronounced as a woman nears meno- options for women undergoing pelvic radiation.34 pause.43,44 The more subtle challenge facing oncologists is As more data emerge regarding the threat to fertility determining in which patients and for how long standard posed by specific pharmacological agents, chemotherapy therapy can be delayed to accommodate fertility preserva- protocols may be modified to avoid potentially gonado- tion. It has been proposed that women with breast cancer toxic side effects in young patients. Chemotherapeutic can delay treatment for up to 1 month to initiate hormo- agents targeting rapidly dividing cells are damaging to nal stimulation and oocyte retrieval for either oocyte or germ cells, with alkylating agents having particularly toxic embryo cryopreservation.8,11,45,46 There is also some evi- effects on ovarian tissue.33,35-37 Studies in patients with dence suggesting that breast cancer patients who will ulti- urological tumors or breast cancer suggest the feasibility mately undergo a course of tamoxifen treatment can delay of treatment modification to help minimize reproductive this antihormonal therapy until after a pregnancy.47 tract toxicity; these modified regimens may be preferable Although estrogen receptor-positive tumors are hormo- Fertility Preservation Cancer Patients/Redig et al nally driven, there is no evidence directly linking preg- scrotal ultrasound revealed a 3-cm heterogeneous left tes- nancy after breast cancer with an increased incidence of ticular lesion, prompting a referral to a urologist. Repeat physical examination confirmed the presence of anindurated, nontender, left testicular mass. Serum tumor marker levels revealed normal alpha-fetoprotein, beta- As demonstrated by the series of case discussions that fol- hCG, and LDH levels. At that time, the patient was coun- low, incorporating fertility preservation into cancer care seled regarding treatment options, and a recommendation requires flexibility on a case-by-case basis to consider a was made for left radical orchiectomy. In addition, he was patient’s wishes as well as the optimal course of therapy encouraged to undergo sperm cryopreservation before sur- gery. He agreed to pursue each of these procedures. Thepatient noted upon questioning that he was engaged and that he and his fiancee had been trying to achieve a preg- A 34-year-old woman presented with an isolated nancy for 1 year without success. He also reported that his 4-cm, firm, left breast mass. After visualization by ultra- fiancee had recently seen a reproductive endocrinologist sound and mammogram, core biopsy was performed, for evaluation of her reproductive health. The oncofertil- which demonstrated estrogen and progesterone receptor- ity patient navigator was contacted, and she helped negative and HER2 negative infiltrating ductal carci- arrange semen analysis testing with concurrent sperm cry- noma. Treatment planning was discussed with the patient opreservation. The patient provided 2 separate semen and included timing of chemotherapy, lumpectomy ver- samples for cryopreservation, each with an appropriate sus mastectomy, and the use of radiation therapy. The duration of 2-3 days of preceding abstinence. Both semen patient opted for primary surgery with lumpectomy, fol- analyses revealed normal ejaculate volume, severely low lowed by chemotherapy and radiation. Fertility preserva- sperm concentration (<100,000 sperm per mL), a moder- tion was also discussed, and the patient, who was single ately low percentage of sperm with motility, and a moder- and had no children, stated that she would want to pursue ately low percentage of sperm with normal morphology.
as many options as possible to try to have a child after her A total of 6 vials of sperm were cryopreserved, and a test treatment. After meeting with the surgical oncologist, thepatient met with an oncofertility patient navigator, and thaw revealed that 25% of the sperm had progressive mo- her case was discussed with the multidisciplinary oncofer- tility post-thaw. The patient’s case was subsequently pre- tility team that included the patient’s oncologists, a repro- sented at the multidisciplinary oncofertility grand rounds, ductive endocrinology infertility specialist, and the attended by his urologist, his fiancee’s reproductive endo- patient navigator. The patient then met with the repro- crinologist, and the oncofertility patient navigator. A rec- ductive endocrinology infertility specialist who discussed ommendation was made for the couple to undergo IVF fertility preservation options, including embryo cryopre- with intracytoplasmic sperm injection (ICSI), given the servation, oocyte cryopreservation, and ovarian tissue cry- severe male factor infertility present.
opreservation. The patient opted for embryo and oocyte The patient underwent left radical orchiectomy, cryopreservation, and oral contraceptives were started im- revealing a nonseminomatous mixed germ cell tumor.
mediately in preparation for oocyte retrieval after surgery.
Postoperative imaging revealed a normal chest x-ray and On final pathology, all lymph nodes and margins were no evidence of retroperitoneal lymphadenopathy, consist- noted to be free of tumor cells. During her 4-week recov- ent with clinical stage I disease. After meeting with a med- ery from surgery, the patient underwent successful ovarian ical oncologist and discussing treatment options, the stimulation and oocyte harvest, which resulted in the cry- patient opted for primary platinum-based chemotherapy opreservation of several oocytes and 4 embryos using an consisting of 2 cycles of bleomycin, etoposide, and cispla- anonymous sperm donor. The patient subsequently began tin. Upon completion of chemotherapy, he underwent se- adjuvant chemotherapy to be followed by radiation, and rial semen testing every 6 months for 2 years. Each semen she intends to pursue a pregnancy in the future with her analysis showed normal ejaculate volume with azoosper- mia. Two years after completion of chemotherapy, thecouple underwent IVF/ICSI using his cryopreserved Fertility preservation and testicular cancer sperm, and a singleton pregnancy resulted.
A 28-year-old single male presented to his internist This case accentuates several important points. First, for evaluation of a painless, firm, left testicular lump. A men affected by cancer may not initially volunteer their efforts to achieve a pregnancy or express their desire for yet become pregnant, although her periods have returned.
future paternity. It is imperative that the urologist or The patient and her husband are now discussing the possi- oncologist discuss the potential effects of cancer and can- bility of working with a reproductive endocrinologist to cer therapy with the patient, preferably before initiation attempt a pregnancy using their cryopreserved embryos. If of treatment. Second, many males diagnosed with cancer the patient’s uterus is determined to be too fibrotic postra- present concurrently with impaired semen parameters.
diation to sustain a pregnancy, they have decided not to These changes may derive from a variety of factors, pursue the use of a surrogate and may instead investigate including fever, cytological immune response, hypogo- nadism, and congenital or acquired testicular abnormal-ities. Finally, surgical therapy and chemotherapy may result in persistent azoospermia, further highlighting the Each of the above cases illustrates the means by which fer- importance of offering sperm cryopreservation before tility preservation can be integrated into the care of cancer patients. In all cases, the success of such measures dependsupon early and open communication with patients, flexi- bility in scheduling appointments and procedures for A 38-year-old woman with a history of hemorrhoids both cancer care and fertility preservation, and the pres- noticed bright red blood in her stool for 6 months. When ence of a multidisciplinary oncofertility team that can see the bleeding did not stop and became associated with ab- patients and discuss their cases on short notice. Current dominal pain and intermittent constipation, she under- guidelines issued by the professional bodies representing went a colonoscopy which revealed a suspicious mass in both oncologists and fertility specialists underscore the the rectum. Biopsy results demonstrated high-grade ade- importance of clear discussion regarding available inter- nocarcinoma, and a CT scan of the chest, abdomen, and ventions.51,52 The 2005 report of the ethics committee of pelvis indicated disease had spread to some local lymph the American Society of Reproductive Medicine (ASRM) nodes. No evidence of disease was seen in other organs. At states that physicians should inform cancer patients about the time of diagnosis, the patient had a 3-year-old daugh- options for fertility preservation—recognizing that, to ter, and she and her husband had been trying to conceive date, the only established techniques for doing so include sperm or embryo cryopreservation. The ASRM guidelines Treatment for stage III rectal cancer involves surgery further emphasize that experimental techniques, includ- as well as preoperative chemotherapy and radiation to the ing oocyte or ovarian tissue cryopreservation, should be pelvis. In this case, pelvic radiation was the most signifi- conducted with the oversight of an Institutional Review cant threat to future fertility, and options, including pre- Board.51 In 2006, the American Society of Clinical On- treatment oophoropexy to move the ovaries away from cology (ASCO) Recommendations on Fertility Preserva- the site of maximum radiation, were discussed with the tion in Cancer Patients were published.52 Key to these patient and her husband. In addition, the decision was guidelines was an awareness that cancer patients are inter- made to use a 5-FU-based chemotherapy regimen instead ested in information regarding fertility, and that early of the more gonadotoxic oxaliplatin. After meeting with intervention and discussion are critical to ensure future her surgeon, the patient was referred to the oncofertility reproductive success. Similar to the ASRM report, these team, where additional options for oocyte or embryo cry- recommendations also identify sperm and embryo cryo- opreservation were also discussed. The patient opted for preservation as the options known to be most successful.
oocyte retrieval and embryo cryopreservation before her As greater numbers of young cancer patients are suc- scheduled oophoropexy and subsequent neoadjuvant cessfully treated, it is increasingly important for the medical chemotherapy and radiation. Dosimetry was specified to community to address the long-term needs of the cancer minimize exposure of the uterus and ovaries to radiation.
survivor. The oncologist has the greatest ability to initiate At the time of surgery, 8 weeks after chemoradiation, a conversations about disease management, treatment 22-cm section of distal colon and rectum were removed, options, and issues related to life after cancer; thus, it is and margins were declared free of tumor. Thirteen meso- essential that oncologists become familiar with the growing rectal lymph nodes showed no evidence of residual cancer, field of fertility preservation. Not only can several distinct and the patient recovered without complications. To date, options be discussed with patients and incorporated into 18 months after the completion of therapy, she has not the multidisciplinary steps of cancer treatment, but doing Fertility Preservation Cancer Patients/Redig et al so can also immeasurably enrich patients’ lives as cancer 11. Agarwal SK, Chang RJ. Fertility management for women survivors. To facilitate this goal, the Oncofertility Consor- with cancer. Cancer Treat Res. 2007;138:15-27.
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