RCT of Fixed vs Titrated Letrozole in Breast Cancer Patient Undergoing IVF
Condition: Breast Cancer; Infertility
MeSH terms: Breast Neoplasms; Infertility
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to compare two different ways to administer Letrozole to
      determine their effectiveness in blocking estrogen production during ovarian stimulation in
      patients with breast cancer prior to chemotherapy/radiotherapy so that oocytes or embryos can
      be cryopreserved and patients can possibly achieve a pregnancy after the treatment of breast
      cancer.

      During standard ovulation stimulation, the estrogen levels will exceed normal levels and may
      reach 10 times the normal level for a 2 week period. This may not be desirable in breast
      cancer patients. The study hopes to determine if the investigators can stimulate oocyte
      development in the conventional way and administer different doses of Letrozole as the
      oocytes develop, to keep estradiol levels low, increase the number of oocytes the
      investigators are able to recover, and improve the quality of those oocytes.
    

Detailed description: 
      IVF is a process which involves a schedule of injectable medication to recruit several
      follicles, each containing an egg, to be retrieved under ultrasound guidance where they can
      be fertilized. Embryos are then selected to be transferred back into the patient's uterus or
      are cryopreserved and transferred at a later date.

      Letrozole is a potent and highly selective third generation aromatase inhibitor that was
      developed in the early 1990's. Aromatase is an enzyme of the cytochrome P-450 superfamily and
      the product of the CYP19 gene, which catalyzes the reaction that converts androgenic
      substances to estrogens in many tissues, including the granulosa cells of ovarian follicles.
      Letrozole competitively inhibits the activity of the aromatase enzyme and has a half-life of
      approximately 48 hours. Because of its potent, sustained suppression in the plasma levels of
      estradiol, this drug has been recently found to be superior to tamoxifen in the treatment of
      advanced-stage post-menopausal breast cancer. Conventional ovarian stimulation often results
      in very high estrogen levels. Since the high estrogen levels are often unsafe for breast
      cancer patients, fixed dose aromatase inhibitor protocols with Letrozole were developed, to
      achieve effective ovarian stimulation with reduced estrogen levels to prevent tumor
      progression and short-term cancer recurrence.

      A fixed dose of Letrozole has been used off-label as an ovulation induction agent in many
      centers to stimulate egg development for infertile couples and patients prior to undergoing
      chemotherapy for estrogen sensitive cancers.

      The purpose of our study is to determine if titrated dose Letrozole in comparison to fixed
      dose Letrozole during gonadotropin stimulation in IVF in breast cancer patients results in
      lower estradiol levels and higher mature oocyte yield.

      In patients who are scheduled to undergo treatment with IVF for fertility preservation due to
      breast cancer, we would like to prospectively randomize them to fixed dose vs. titrated dose
      of Letrozole. Due to time restraints for chemotherapy patients may present for ovarian
      stimulation prior to Day 2 of their menstrual cycle. If this were to occur, Ganirelix may be
      started to suppress the pituitary hormones for down regulation prior to starting stimulation
      medications until day 2 of menstrual bleeding. Eligible subjects will be fully informed about
      the nature of the trial. Subjects could be enrolled for IVF treatment at any point after
      breast cancer diagnosis following surgery but before the initiation of chemotherapy, if
      chemotherapy has been prescribed by their oncologist. After obtaining written informed
      consent, the subjects will be screened based on inclusion/exclusion criteria, medical and
      infertility history, Day 2/3 FSH and estradiol, physical and gynecological examination,
      oncology clearance and the Center's standard screening evaluations for IVF patients. A
      thorough gynecologic and endocrinologic evaluation will be performed before the start of any
      treatment. Laboratory assessments will include CBC, chemistry and lipid profile (see attached
      history and physical form). Vital signs including blood pressure, pulse, and weight will be
      assessed at baseline (prior to start of stimulation medication), with preoperative
      evaluation, on day of egg retrieval, and with post retrieval visits.

      Patients will have serum blood tests for bHCG, FSH, AMH, Estradiol, and LH and vaginal
      sonogram on the second day of menstrual bleeding. Start of stimulation medication will
      proceed only with documentation of a serum negative pregnancy test. Patients will only be
      eligible to participate in the study for one cycle of in vitro fertilization.

      Patients who elect to participate in the study will be provided with gonadotropin
      medications.

      The starting dose of gonadotropins for both study groups would be determined by the patients'
      age and by antral follicle counts assessed by transvaginal ultrasound at the time of initial
      consultation. See below:

      Age <35 , Antral follicle Count >15 gonadotropin dose 225 IU (150 IU FSH + 75 IU HMG; Age
      <35, Antral follicle Count <15 gonadotropin dose 300 IU (150 IU FSH + 150 IU HMG; Age 35-39,
      Antral follicle Count >10 gonadotropin dose 300 IU (150 IU FSH + 150 IU HMG; Age 35-39,
      Antral follicle Count <10 gonadotropin dose 450 IU (225 IU FSH + 225 IU HMG; Age>40
      Independent of antral follicle count, gonadotropin dose 450 IU (225 FSH + 225 IU HMG);

      All patients would also be given a daily medication to prevent them from ovulating
      (Ganirelix), no later than cycle day #7 and continuing until HCG administration.

      Group#1-Fixed Letrozole Group: Provided their blood tests and sonograms were within normal
      limits, patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily
      (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day
      of their menstrual cycle (Current Letrozole protocol at CRMI). Patients will be monitored
      with daily blood tests for estradiol and LH and sonogram every 1-3 days. Adjustments to
      gonadotropin dosing will be made as per usual protocol for IVF. Letrozole dose will not
      change and will continue for two weeks after egg retrieval.

      Group #2-Titrated Letrozole Group: Provided their blood tests and sonograms were within
      normal limits, patients who are randomized to the titrated dose of Letrozole, will start
      gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle
      stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be
      added to the stimulation in the following titrated regimen:

      Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg;
      Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;

      The maximal starting dose of Letrozole will be 5 mg, regardless of the initial estradiol
      level. The Letrozole dose may be reduced if the appropriate suppression of estradiol occurs.
      The maximal increase or decrease in Letrozole dose will be 2.5 mg/ day. Patients will be
      monitored with blood tests for estradiol and LH and sonograms starting on the second day of
      gonadotropin stimulation and every 1-3 days to monitor response and adjust medication dose as
      per our usual IVF protocol. Letrozole will be stopped for both groups on the day that HCG is
      given and resumed after egg retrieval. All patients will stay on the same dose of Letrozole
      that was required for their last day of ovarian stimulation for 2 weeks after stimulation to
      keep estradiol levels at a minimum. In addition, patients will have serum estradiol levels
      drawn weekly for 2 weeks after stimulation. Follow-up vital signs will be recorded along with
      CBC, liver function panel, and cholesterol panel 2 weeks after stimulation. They will also be
      asked to return 6 months to 1 year after completion of chemotherapy for AMH and FSH levels to
      evaluate ovarian reserve, and then followed on a yearly basis by phone/mail questionnaire or
      in person with an annual gynecological examination.

      All study patients will be provided with an emergency 24-hour phone number to reach a
      physician to report adverse reactions to medications, and these physicians will file adverse
      event report forms to the principal investigator and data safety monitoring board. In
      addition, they will be asked to report any adverse reactions to medications during follicular
      monitoring sonograms. All decisions regarding daily medication doses will be determined by
      the study principal investigator. Otherwise, the treatment of ovarian stimulation, egg
      retrieval, and cryopreservation is identical to non-study patients undergoing ovarian
      stimulation, oocyte retrieval, and embryo/oocyte cryopreservation.

      Two weeks after retrieval, follow-up instructions will be reviewed. Patients will be advised
      to refrain from embryo transfer for a minimum of 2 years after chemotherapy. Patients will
      not be permitted to undergo embryo transfer for a minimum of one year after completing
      chemotherapy and only after clearance for pregnancy has been obtained from their medical
      oncologist. Patients will be followed for five years on an annual basis with a follow-up
      telephone call from one of the investigators inquiring about health status (see patient
      follow-up data sheet). A pregnancy registry will be created for any pregnancy occurring
      following enrollment in the study. Detailed pregnancy outcome will be collected between age
      2-5 years (see baby follow-up data sheet attached).
    

Intervention name(s): Letrozole; Letrozole
Intervention type(s): Drug; Drug
Intervention description(s): Letrozole titrated regimen may be started on day 2 of menstrual cycle:
Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;; Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle
Other intervention name(s): Femara- trade name; Femara- trade name
Intervention MeSH terms: Letrozole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Letrozole; IVF (in vitro fertilization); Cryopreservation; Fertility Preservation; Breast Cancer