Correspondence

Preservation of Fertility in Patients with Cancer

N Engl J Med 2009; 360:2680-2683June 18, 2009

Article

To the Editor:

With regard to the review article by Jeruss and Woodruff (Feb. 26 issue)1: we appreciate the increased attention to options for the preservation of fertility in people with cancer; however, it is important to inform readers of the evidence-based guidelines on this topic that were published in 2006 by a committee convened by the American Society of Clinical Oncology (ASCO).2 The ASCO guidelines were based on a systematic review of the literature and formal procedures for guideline creation, including composition of the committee, critique by outside experts, and review by ASCO administrative bodies. Per ASCO policy, these guidelines will also be updated periodically with the use of the same rigorous procedures. Many of the specific recommendations in the review by Jeruss and Woodruff are quite controversial, and their approach should be recognized as one among many in an evolving field.

Stephanie J. Lee, M.D., M.P.H.
Fred Hutchinson Cancer Research Center, Seattle, WA 98109
sjlee@fhcrc.org

for the ASCO Fertility Preservation Guidelines Committee

2 References

1
Jeruss JS, Woodruff TK. Preservation of fertility in patients with cancer. N Engl J Med 2009;360:902-911
Full Text | Web of Science | Medline

2
Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006;24:2917-2931[Erratum, J Clin Oncol 2006;24:5790.]
CrossRef | Web of Science | Medline

To the Editor:

In their review, Jeruss and Woodruff state that “children undergoing chemotherapy can receive GnRH [gonadotropin-releasing hormone] agonists.” However, GnRH agonists are given to young women — not to children — before chemotherapy to simulate the prepubertal hormonal milieu,1,2 since the risk of premature ovarian failure after chemotherapy is significantly lower among children than among women.1,2 Recent summaries of the published studies on the use of GnRH agonists in parallel with chemotherapy for fertility preservation have shown that the rate of premature ovarian failure among the young women who received GnRH agonists was 9 to 11% versus a rate of 55 to 59% among controls.1,2 Furthermore, two recent prospective, randomized studies showed “evidence of [a] protective effect of GnRH [agonists] on ovarian function” in patients with breast cancer and a significant decrease in the gonadotoxic effects of chemotherapy.3,4 Possible pathophysiological mechanisms were put forward.1

Zeev Blumenfeld, M.D.
Technion, 31096 Haifa, Israel
z_blumenfeld@rambam.health.gov.il

4 References

1
Blumenfeld Z, von Wolff M. GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy. Hum Reprod Update 2008;14:543-552
CrossRef | Web of Science | Medline

2
Beck-Fruchter R, Weiss A, Shalev E. GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data. Hum Reprod Update 2008;14:553-561
CrossRef | Web of Science | Medline

3
Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril 2009;91:694-697
CrossRef | Web of Science | Medline

4
Sverrisdottir A, Nystedt M, Johansson H, Fornander T. Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res Treat 2009 January 20 (Epub ahead of print).

To the Editor:

Although the review article by Jeruss and Woodruff provides an overview of fertility preservation, some clarifications are essential. Ovarian stimulation with letrozole has outcomes that are similar to those of standard protocols that involve significantly less estrogen exposure.1 After ovarian stimulation with letrozole, rates of breast-cancer recurrence do not increase at up to 5 years of follow-up.2 The typical gap of 6 to 8 weeks between breast surgery and adjuvant chemotherapy may allow for multiple cycles without delaying chemotherapy. Since the first report of autologous ovarian transplantation,3 no recurrences of cancer have been reported. In most nonmetastatic cancers affecting young women, including breast cancer, ovarian involvement is rare. When closer surveillance is required, ovarian tissue can be transplanted subcutaneously (although this experimental procedure has not yet been performed in carriers of BRCA mutations).4 Although hundreds of children have been conceived with the use of frozen oocytes,5 in vitro maturation of primordial follicles is a daunting task. This complex process takes months in the ovary. Even if it becomes possible in humans, epigenetic changes due to protracted culture would be of concern. Both ASCO and the American Society for Reproductive Medicine (ASRM) have issued multidisciplinary guidelines that should be followed when considering fertility preservation.

Kutluk Oktay, M.D.
New York Medical College, Valhalla, NY 10595
koktay@fertilitypreservation.org

Kenny Rodriguez-Wallberg, M.D., Ph.D.
Karolinska Institutet, SE-171 77 Stockholm, Sweden

Leslie Schover, Ph.D.
M.D. Anderson Cancer Center, Houston, TX 77030

5 References

1
Oktay K, Hourvitz A, Sahin G, et al. Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy. J Clin Endocrinol Metab 2006;91:3885-3890
CrossRef | Web of Science | Medline

2
Azim AA, Costantini-Ferrando M, Oktay K. Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: a prospective controlled study. J Clin Oncol 2008;26:2630-2635
CrossRef | Web of Science | Medline

3
Oktay K, Karlikaya G. Ovarian function after transplantation of frozen, banked autologous ovarian tissue. N Engl J Med 2000;342:1919-1919
Full Text | Web of Science | Medline

4
Oktay K, Buyuk E, Veeck L, et al. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet 2004;363:837-840
CrossRef | Web of Science | Medline

5
Oktay K, Cil AP, Bang H. Efficiency of oocyte cryopreservation: a meta-analysis. Fertil Steril 2006;86:70-80
CrossRef | Web of Science | Medline

To the Editor:

Jeruss and Woodruff call attention to the plight of the increasing numbers of young survivors of cancer who undergo treatment at the cost of their future fertility. However, it is disappointing that the authors neglect to call attention to the particular challenges with younger adolescent boys, whose bodies are as fertile as those of adults, but whose minority presents considerable legal and cultural hurdles when it comes to sperm cryopreservation.1 Spermarche does not always correlate with signs of adrenarche,2-4 so if clinicians offer sperm banking only for boys who appear to be postpubertal on examination, they will miss patients who are already fertile, despite their low Tanner stage. To say that “options for fertility preservation in the pediatric population largely overlap those that are available for adults” and that postpubertal boys should be advised to bank sperm, but that “there are no established options for the preservation of fertility in prepubertal boys” is therefore a misleading oversimplification.

Barbara M. Chubak, M.D.
Cleveland Clinic, Cleveland, OH 44195
bchubak@gmail.com

4 References

1
Schover LR, Brey K, Lichtin A, Lipshultz LI, Jeha S. Oncologists' attitudes and practices regarding banking sperm before cancer treatment. J Clin Oncol 2002;20:1890-1897
CrossRef | Web of Science | Medline

2
Nysom K, Pedersen JL, Jorgensen M, et al. Spermaturia in two normal boys without other signs of puberty. Acta Paediatr 1994;83:520-521
CrossRef | Web of Science | Medline

3
Nielsen CT, Skakkebaek NE, Richardson DW, et al. Onset of the release of spermatozoa (spermarche) in boys in relation to age, testicular growth, pubic hair, and height. J Clin Endocrinol Metab 1986;62:532-535
CrossRef | Web of Science | Medline

4
Richardson DW, Short RV. Time of onset of sperm production in boys. J Biosoc Sci Suppl 1978;5:15-25
CrossRef | Medline

To the Editor:

Recommendations about options to preserve fertility in young girls who have recently received a diagnosis of cancer should include an assessment of ovarian reserve (the size of the primordial follicle pool), the risk to future fertility, and the established methods available for each patient.1 The review by Jeruss and Woodruff, while welcome, is potentially misleading to clinicians in some important areas. In an individual patient, the risk of the development of premature menopause depends on the nature of the treatment planned and the ovarian reserve at presentation. Most girls who are treated for cancer will be fertile.1 Radiotherapy to a field that includes the pelvis significantly increases the risk of premature ovarian failure.2 Chemotherapy has variable effects on ovarian reserve, depending on the agent and total dose delivered.1

Procedures for fertility preservation are preferably completed before the start of chemotherapy and radiotherapy. When cancer treatment cannot be delayed, cryopreservation of ovarian tissue can be performed at a later date, before potentially sterilizing treatment.3 In patients who have been exposed to chemotherapy, aspiration of mature oocytes for embryo or egg freezing is ineffective and potentially unsafe.4 Techniques for detecting cancer cells in ovarian tissue are available for some patients with leukemia and may increase the safety of ovarian transplantation.5

Dror Meirow, M.D.
Chaim Sheba Medical Center, 52662 Tel Hashomer, Israel
meirow@post.tau.ac.il

W. Hamish Wallace, M.D.
Royal Hospital for Sick Children, Edinburgh EH9 1LF, United Kingdom

5 References

1
Wallace WH, Anderson RA, Irvine DS. Fertility preservation for young people with cancer: who is at risk and what can be offered? Lancet Oncol 2005;6:209-218[Erratum, Lancet Oncol 2005;6:922.]
CrossRef | Web of Science | Medline

2
Wallace WH, Thomson AB, Saran F, Kelsey TW. Predicting age at ovarian failure following radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Phys 2005;62:738-744
CrossRef | Web of Science | Medline

3
Meirow D, Levron J, Eldar-Geva T, et al. Monitoring the ovaries after autotransplantation of cryopreserved ovarian tissue: endocrine studies, in vitro fertilization cycles, and live birth. Fertil Steril 2007;87(2):418.e7-418.e15.

4
Meirow D, Schiff E. Appraisal of chemotherapy effects on reproductive outcome according to animal studies and clinical data. In: Parenthood after cancer: today's options and tomorrow's hopes. Journal of the National Cancer Institute monographs. No. 34. Bethesda, MD: Journal of the National Cancer Institute, 2005:21-5.

5
Meirow D, Hardan I, Dor J, et al. Searching for evidence of disease and malignant cell contamination in ovarian tissue stored from hematologic cancer patients. Hum Reprod 2008;23:1007-1013
CrossRef | Web of Science | Medline

Author/Editor Response

We thank Lee and Oktay et al. for noting the ASCO and ASRM guidelines for fertility preservation.1,2

In response to Oktay et al.: letrozole for ovarian stimulation may be an option in the future, and its efficacy should be demonstrated through multicenter, randomized trials in order to better understand the advantage this drug may have over traditional regimens for ovarian stimulation in terms of safety and the effect on rates of breast-cancer recurrence. A gap of 6 to 8 weeks between surgery and chemotherapy for breast cancer falls outside the typical 4-week period between treatments. With regard to the transplantation of ovarian tissue, we maintain that this would be a less desirable option in carriers of BRCA mutations and patients with cancer because of the risk of reexposure to malignant cells. A global effort to report all cases of ovarian tissue transplantation, including methods, success rates, and adverse events, is the first step toward understanding the efficacy and safety of the procedure. We agree that in vitro follicle maturation is a complex process, and this technique is being actively studied in the laboratory setting.

In response to Blumenfeld: the possible usefulness of GnRH agonists for fertility preservation has been controversial.3,4 This controversy may be resolved in the near future through recent reports on prospective trials and trials that are ongoing.5 Since GnRH agonists are noninvasive, they would be acceptable to many physicians and patients; however, if the treatment is not effective or is effective only in some individual cases, patients will need alternatives that give the best probability of fertility preservation.

We appreciate the point raised by Chubak which highlights the importance of accurate assessment of sexual maturity in the pediatric population; this can be a difficult task, although it should be possible. Experimental techniques are under development for prepubertal boys.

In our article, we discussed all the points mentioned by Meirow and Wallace, and we reached the same conclusions. Thus, since we are in complete agreement, we cannot comment on any issue that was perceived as being misleading.

The threat to fertility that cancer treatments pose to young patients can be significant, and, if possible, mature techniques such as embryo banking and sperm banking should be considered before the initiation of cancer therapy. Raising the awareness of fertility-preservation options among clinicians and young patients with cancer is critical. New techniques are under development, and they may expand the range of options in the future. Where possible, multicenter studies should be initiated to ensure the most rapid completion of high-quality research so that authoritative guidelines for intervention can be created.

Jacqueline S. Jeruss, M.D., Ph.D.
Teresa K. Woodruff, Ph.D.
Northwestern University Feinberg School of Medicine, Chicago, IL 60611
tkw@northwestern.edu

5 References

1
Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006;24:2917-2931[Erratum, J Clin Oncol 2006;24:5790.]
CrossRef | Web of Science | Medline

2
Ethics Committee of the American Society for Reproductive Medicine. Fertility preservation and reproduction in cancer patients. Fertil Steril 2005;83:1622-1628
CrossRef | Web of Science | Medline

3
Oktay K, Oktem O. Fertility preservation medicine: a new field in the care of young cancer survivors. Pediatr Blood Cancer 2009 March 19 (Epub ahead of print).

4
Clowse ME, Behera MA, Anders CK, et al. Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis. J Womens Health (Larchmt) 2009;18:311-319
CrossRef | Web of Science | Medline

5
Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril 2009;91:694-697
CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1
Erin F. Wolff, Marybeth Hughes, Maria J. Merino, James C. Reynolds, Jeremy L. Davis, Craig S. Cochran, Francesco S. Celi. (2010) Expression of Benign and Malignant Thyroid Tissue in Ovarian Teratomas and the Importance of Multimodal Management as Illustrated by a BRAF -Positive Follicular Variant of Papillary Thyroid Cancer. Thyroid 20:9, 981-987
CrossRef
2
Danny M. Rabah, Iman H. Wahdan, Abdelmalek Merdawy, Bassem Abourafe, Mostafa A. Arafa. (2010) Oncologists’ knowledge and practice towards sperm cryopreservation in Arabic communities. Journal of Cancer Survivorship 4:3, 279-283
CrossRef