PROtecting Ovaries and Fertility During Chemotherapy - The PROOF Trial: A Randomized Controlled Trial of Gonadotropin Releasing Hormone Agonist (GnRHa) for Fertility Preservation in Oncology Patients
Fertility preservation is defined as the maintenance of one's ability to reproduce.
The hypothesis for this study is that medical treatment (GnRHa) will help female cancer
patients, receiving sterilizing chemotherapy, preserve their ovarian function and therefore
fertility. This study is a feasibility trial of the drug (GnRHa)vs placebo in female cancer
patients receiving gonadotoxic chemotherapy between the ages of 18 and 38 who wish to
The objective of the feasibility trial is to determine the feasibility of a definitive study
to answer this question and also to define the required parameters needed to design the
definitive study such as the observable difference in ovarian failure between the drug and
placebo groups. The same protocol will be followed as proposed for the definitive trial but
with a smaller sample size.
This pilot study will be conducted at the Ottawa Hospital Regional Cancer Centre/Division of
Reproductive Medicine of Department of Obstetrics and Gynecology, University of Ottawa and
the Cancer Centre of Southeastern Ontario/Division of Reproductive Medicine of Department of
Obstetrics and Gynecology, University of Ottawa.
The planned trial intervention is trimonthly (every 3 months) administration of depot GnRHa
(Leuprolide acetate (LA) 11.25 mg intramuscularly) or placebo. Injections would start prior
to initiation of chemotherapy, in the luteal phase of the menstrual cycle preceding
chemotherapy, and will continue until cessation of chemotherapy (maximum of 6 months or 2
injections). Since only adjuvant/curative chemotherapy patients will be enrolled,
chemotherapy will last a maximum of six months.
Subjects will be randomized, with concealed allocation, to either GnRHa or placebo.
Subjects and investigators will be blinded to the intervention administered.
Inclusion criteria: Women who are
1. between ages 18 to 38;
2. who will be undergoing gonadotoxic (sterilizing) curative/ adjuvant chemotherapy for
early stage disease; and
3. have provided informed consent. All subjects will be enrolled from the Ottawa Hospital
Regional Cancer Institute (OHRCC) and the Cancer Center of South Eastern Ontario at
Kingston General Hospital (CCSEO). Gonadotoxic chemotherapy includes alkylating /
anthracycline agents eg. cyclophosphamide.
Exclusion criteria: Women who;
1. have advanced stage disease and/or whose median survival is expected to be less than 6
2. have cancer of the ovaries, uterus, or fallopian tubes;
3. have clinical or biochemical evidence of diminished ovarian reserve (recent shortening
of cycles < 24 days between menses, age > 38, elevated serum FSH (follicular
stimulating hormone)> 15 IU/L, or low antral follicle count (AFC- number of
follicles less than 10 mm on day 2 or 3 of natural menses) on baseline pelvic
ultrasound (<5) or elevated day 2 or 3 estradiol (> 280 pmol/ml);
4. have previously received chemotherapy or abdominal/pelvic radiation or have planned to
receive abdomino/pelvic radiation;
5. are pregnant;
6. have contraindications to intramuscular injections; or 7) have a history of fractures
secondary to/or documented osteoporosis.
Outcomes: Subjects will be assessed at baseline, monthly (for adverse effects only) during
active intervention, and at 0, 3, 6, 9, and 12 months post cessation of chemotherapy and
treatment (GnRHa/ placebo) for predictors of ovarian reserve.
The primary outcome is protection against ovarian failure at 12 months post chemotherapy.
This is measured by resumption of regular menstrual cycles (every 24 -35 days) with
documentation of ovulation by biochemistry (progesterone levels) over a minimum of three
Secondary outcomes will include sonographic (biophysical) and biochemical markers of ovarian
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment
Protection against ovarian failure
12 months post Chemo therapy
Sonya Kashyap, MD MSc
Ottawa Hospital Research Institute
Canada: Health Canada