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Additional Considerations for COS in Cancer Patients: Protocol Challenges

Which exact stimulation protocol is best? A controversy in the field revolves around the hypothesis that the transient elevations of estrogen during an IVF cycle may stimulate tumor growth, thus increasing the risk of treatment failure or cancer recurrence.  However, this is a hypothetical risk — no studies have demonstrated that a single IVF cycle increased the risk of poor oncologic outcomes.

Modified IVF protocols:

  • Some providers attempt to mitigate the peak estrogen levels during stimulation, using a modified IVF protocol developed by Oktay et al1.
  • This modified protocol uses anti-cancer hormonal therapy during an “Antagonist Cycle” to mitigate the peak estrogen levels during the stimulation2.

Routine IVF protocols:

  • Other providers use routine COS protocols from the infertility literature, even in women with a hormone-sensitive cancer, arguing that these standard treatments may yield more embryos or oocytes than a novel protocol.
  • For example, the FertiPROTEKT network, a coalition of approximately 70 centers for reproductive medicine in Europe, uses standard IVF protocols such as the “short-agonist protocol” with GnRH-agonist, or an antagonist protocol2.
  • Another large fertility preservation center in New York reports using a standard ‘antagonist’ stimulation protocol for their cancer patients, even those with hormone-sensitive carcinoma3.

an illustration of a hormone shot and a cell
How can we rapidly induce a menstrual cycle? In routine IVF cycles for infertility, timing the start of an IVF cycle can be manipulated with oral contraceptive pills or GnRH-agonists started in the luteal phase of the prior cycle.  However, in women with cancer, minimizing the time needed for stimulation is crucial.  Most COS cycles are essentially ‘spontaneous antagonist’ cycles, starting when the women’s menses begin.  Therefore, it is important to know when the menses are due to begin OR induce a cycle with medications.  Here are some considerations:

Try to determine where she is in her current cycle.

  • For women with a history of irregular cycles or who do not have a uterus, determining where they are in their cycle can be challenging. Even in women with previously regular cycles, their cycle may be unpredictable in the months after a cancer diagnosis, possibly related to stress, etc.
  • Consider serial lab tests (FSH, estradiol, progesterone levels) and/or a pelvic ultrasound.
  • If it seems like she is due for a cycle in the coming week, consider waiting for her spontaneous cycle.

If the timing is not convenient, consider these options:

  • Provera – consider 7-10 day course to induce a cycle, especially in women who appear to be anovulatory.  This is not recommended in women with breast cancer who are progesterone-receptor positive.
  • GnRH-antagonist – Off-label daily usage of GnRH-antagonist (such as a single dose of 3 mg or 2-3 days of 250 microgram dose) has been shown to be effective in the early follicular4and the luteal5,6 phase to cause immediate suppression of the pituitary-gonadal function.  In the luteal phase, this should cause luteolysis and bleeding. Ovarian stimulation can usually begin 5-7 days after GnRH antagonist treatment.
  • Begin the stimulation during the luteal phase – Bedoschi et al. published a case series involving 2 patients who began COS in the luteal phase – in both cases, oocyte yield was reasonable7. Also, von Wolff published a case series where 12 patients initiate daily 250 microgram doses of GnRH antagonist at the same time as daily subcutaneous gonadotropin administration. They report no significant detriment to outcomes (days of stimulation, number of oocytes retrieved, oocyte maturity, and fertilization rate8.
Are IVF cycles different for women with cancer? Several factors need to be accounted for when predicting the chance of future pregnancy when banking embryos or eggs.  First of all, one must consider the anticipated ‘success’ of a controlled ovarian stimulation (COS) procedure, in terms of stimulation characteristics, oocyte yield, fertilization rates, etc.

Published studies about COS in cancer patients

  • Several case-control studies have been published, looking at the efficacy of COS1,3,9-11.
  • The control groups for these studies are couples with either male or tubal factor infertility.
  • The assumption is that women in these control groups have essentially normal fertility status, which is likely the same as the women with cancer.
  • These studies, in general, demonstrate that COS cycles for women with cancer are similar to those of women without cancer.
  • Quintero et al. concludes from their retrospective study that women with cancer require more gonadotropins and a longer stimulation, but have a higher rate of ‘poor response’ as compared to age-matched controls10.

Conclusions about COS in cancer patients:

  • Protocols:  Most studies report using an antagonist protocol, as this allows the quickest start of stimulation.  However, some patients used a protocol with GnRH-a11.  Some centers used tamoxifen or letrozole for women with hormone-sensitive cancers1, 10-11, and other did not3, 9.
  • Starting dose of gonadotropins:  Some centers tended to be more conservative (lower starting dose) for cancer patients to minimize the risk of ovarian hyperstimulation syndrome (OHSS).  Other centers used standard starting doses, or even slightly higher doses, given that this was likely the couple’s one attempt at COS, and they wanted to minimize the risk of poor response.
  • Gonatropin usage:  For women with cancer, the overall gonadotropin usage was found to be similar in some studies3, 9, higher in one10, and lower in another1.
  • Peak Estradiol: In general, peak estradiol levels appear to be the same or lower in women with cancer, even at centers that do not routinely use letrozole or tamoxifen.
  • Days of stimulation:  The duration of stimulation is similar in women with and without cancer (on average 9-11 days).
  • Medication for trigger: While rare, OHSS can occur in women undergoing ovarian stimulation for fertility preservation, even in cases when letrozole is used and peak estradiol levels are relatively low12, 13. With an antagonist cycle, there is the option of using a GnRH agonist trigger, to minimize the risk of OHSS11. For example many centers use Leuprolide acetate, 1-2 mg SQ12. A GnRH agnoist for trigger can cause a profound and rapid luteolysis and possibly allow for more rapid progresssion to the start of cancer treatments.
  • Number of oocytes retrieved:  In general, the oocyte yield is similar in women with cancer compared to their age-matched control group, though one center reports significantly lower oocyte yield in women with cancer (10 vs 13.9, p<0.02)9.
  • Poor response and cancellations:  Of concern, compared to controls, one study found that the cancellation rate is higher in women with cancer (7.1% vs. 0%)1, and another found that the rate of poor response (<4 oocytes retrieved) was higher in cancer patients (18% vs 4%, p=0.05)10.
  • Method of fertilization: While there is no data to suggest the optimal method of fertilization, some centers use standard ICSI cirteria, while others use ICSI for all embryo banking cases to avoid the risk of failed fertilization.
  • Fertilization rate:  It is difficult to make conclusions about fertilization rates, as many patients freeze oocytes and not embryos.  However, the minimal published data seem reassuring regarding fertilization rates1, 9.
  • Pregnancy rates:  No studies have focused specifically on pregnancy rates, mostly because there haven’t been enough women with cancer who have elected to use their frozen gametes or embryos to attempt pregnancy. See below for estimates of future pregnancy rates.
Can a patient undergo COS after recieving chemotherapy?
  • There is scant published human data evaluating the success of an IVF cycle after a woman has received cytotoxic chemotherapy.
  • One murine model indicated that superovulated mice treated with cyclophosphamide 0-24 days prior to oocyte recovery had significantly reduced fertilization and cleavage rates14.

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;91:3885-90.

2. Lawrenz B, Jauckus J, Kupka M, Strowitzki T, von Wolff M. Efficacy and safety of ovarian stimulation before chemotherapy in 205 cases. Fertil Steril 2010; 94: 2871-3.

3. Knopman JM, Noyes N, Talebian S, Krey LC, Grifo JA, Licciardi F. Women with cancer undergoing ART for fertility preservation: a cohort study of their response to exogenous gonadotropins. Fertil Steril 2009; 91: 1476-8.

4. Nelson LR, Fujimoto VY, Jaffe RB, Monroe SE. Suppression of follicular phase pituitary-gonadal function by a potent new gonadotropin-releasing horomone antagonist with reduced histamine-releasing properties (ganirelix). Fertil Steril 1995; 63:963-9.

5. Hall JE, Bhatta N, Adams JM, Rivier JE, Vale WW, Crowley WF, Jr. Variable tolerance of the developing follicle and corpus luteum to gonadotropin-releasing hormone antagonist-induced gonadotropin with drawal in the human. J Clin Endocrinol Metab 1991;72:993-1000.

6. Kettel LM, Roseff SJ, Chiu TC, et al. Follicular arrest during the midfollicular phase of the menstrual cycle: a gonadotropin-releasing hormone antagonist imposed follicular-follicular transition. J Clin Endocrinol Metab 1991;73:644-9.

7. Bedoschi GM, de Albuquerque FO, Ferriani RA, Navarro PA. Ovarian stimulation during the luteal phase for fertility preservation of cancer patients: case reports and review of the literature. J Assist Reprod Genet;27:491-4.

8. von Wolff M, Thaler CJ, Frambach T, Zeeb C, Lawrenz B, Popovici RM et al. Ovarian stimulation to cryopreserve fertilized oocytes in cancer patients can be started in the luteal phase. Fertil Steril 2009; 92:1360-5.

9. Klock SC, Zhang JX, Kazer RR. Fertility preservation for female cancer patients: early clinical experience. Fertil Steril;94:149-55.

10. Quintero RB, Helmer A, Huang JQ, Westphal LM. Ovarian stimulation for fertility preservation in patients with cancer. Fertil Steril;93:865-8.

11. Michaan N, Ben-David G, Ben-Yosef D, et al. Ovarian stimulation and emergency in vitro fertilization for fertility preservation in cancer patients. Eur J Obstet Gynecol Reprod Biol;149:175-7.

12. Oktay K, Turkcuoglu I, Rodriguez-Wallberg KA. GnRH agonist trigger for women with breast cancer undergoing fertility preservation by aromatase inhibitor/FSH stimulation. Reprod Biomed Online; 20:738-8.

13. Kim J, Steiner AZ, Fritz M, Mersereau JE. Severe ovarian hyperstimulation syndrome after letrozole-gonadotropin stimulation: a case report. J Assist Repro Genet 2012; 29 (2): 127-9.

14. Pydyn EF, Ataya KM. Effect of cyclophosphamide on mouse oocyte in vitro fertilization and cleavage: recovery. Reprod Toxicol 1991;5:73-8.

About the Author

Jennifer Mersereau, MD, MSCI, is an reproductive endocrinologist in the University of North Carolina’s Department of Obstetrics and Gynecology. As the Director of the Fertility Preservation Program, she has extensive experience guiding patients and physicians through the oncofertility experience.

Page last updated March 14, 2012.

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