Clinical trial NCT02429349: Preservation of Ovarian Tissue and Chemo-Radiotherapy
Official title: Surgical Ovarian Preservation in Females Undergoing Chemo-Radiotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Endocrine Disorders of Female Reproductive System
Secondary Infertility
Infertility Involuntary
Lead sponsor: University of Tennessee
Sponsor class: OTHER
First posted: 2015-04-29
Enrollment: 2
Sex: FEMALE
Minimum age (years): 8
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the results of ovarian tissue freezing, such as resumption or initiation of menses (menstruation: the discharge of blood and tissue from the uterus that happens about every 4 weeks in females who are not pregnant) and pregnancy, prior to starting chemotherapy or radiation treatment (commonly used for cancer treatment or for other conditions such as multiple sclerosis, psoriasis, rheumatoid arthritis). Females who are about to undergo chemotherapy or radiation therapy for cancer or these other medical conditions may stop having menses and may not be able to produce a biological child. Girls who have not achieved puberty and are exposed to chemotherapy (alkylating agents) or radiation treatment, the risk is up to 22-50%. In contrast, girls older than 10 years, or who have achieved puberty, experience acute ovarian failure in over 50% of the cases. By freezing and preserving ovarian tissue will help prevent these outcomes. In fact, when you are considered cured of your disease, you will have another surgical procedure where your own ovarian tissue will be transplanted back to you. This surgery will increase the possibility of resuming/initiating menses and the chance to have a pregnancy.

Detailed description: At the present time, freezing of ovarian tissue is considered experimental and so thawing and future use of the tissue to initiate a pregnancy must be performed as part of a research program. With the patient's permission, a portion of her ovarian tissue will be frozen for her own use and a portion will be donated to a research pool.

Twenty subjects/year will be participating in this study.

Participation in this study will last until the patient's ovarian tissue is all used, or the patient decides to drop out of the study, or for the rest of her life. Freezing of ovarian tissue can be done only for research. Thawing and future use of the tissue to start a pregnancy must be done as part of a research program. After the age of 18, the patient will decide how and at what institution she wishes to use her own tissue in the future, for the purposes of becoming pregnant. The number of visits will be decided by the surgical procedure performed. The Investigators will contact the patient by phone, email, or mail until she has turned 18 years old, used her tissue or dropped out of the study (whichever comes first) to follow the patient's medical and fertility status over time and to ask questions about any future use of her frozen tissue and the possible results of the treatment. Depending on the patient's age at the time of enrollment, follow-up might be up to 30 years.

PURPOSE Primary objective: To assess resumption/initiation of menses after surgical ovarian preservation (ovarian tissue explant followed by freezing and autologous transplantation).

Secondary objective: To assess pre- and post-treatment production of various hormones, i.e., anti-mullerian hormone (AMH), insulin-like growth factor-1 (IGF-1), inhibin-B, follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol, by serum and histological measurements.

Tertiary objective: To assess long-term sexual development, fertility competence, and lifespan of ovarian preservation via surgical autotransplant.

RATIONALE Chemotherapy treatment with alkylating agents and/or total body irradiation will prevent normal pubertal development of uterus, ovaries, and breasts because of primary ovarian insufficiency (POI). Explant and autologous transplantation of ovarian tissue will prevent ovarian insufficiency and allow normal sexual development through puberty and fertility competence.

RESEARCH DESIGN Prospective cohort study.

STUDY PROCEDURES Subject Recruitment and Screening- Subjects will be recruited by referral from the St. Jude Children's Research Hospital (SJCRH) and Methodist-Le Bonheur physicians to the Reproductive Medicine clinics held by Dr. Laura Detti. Patients will undergo an informed consent process in accordance with St. Jude Children's Research Hospital (SJCRH) and Methodist-Le Bonheur Institutional Review Boards.

Screening Visit- Complete medical history and physical exam; vital signs, height, and weight. Psychological Consult on impact of therapy.

Laboratory testing- Lab results for Estradiol, follicle stimulating hormone (FSH), luteinizing hormone (LH), Anti-Mullerian hormone (AMH), Inhibin B, will be obtained from the patients' clinical charts. In addition, Electrocardiogram (ECG) (12-lead); Bone age scan (if pre-pubertal), Pelvic ultrasound (transabdominal or transvaginal, depending on the patient's age) will be obtained from the patients' clinical charts. If a pelvic ultrasound has not been obtained prior to surgery, the procedure will be performed under anesthesia prior to the patient undergoing surgery for ovarian tissue harvesting).

Surgical Procedures- Unilateral oophorectomy will be performed by laparoscopy prior to undergoing chemo-radiation treatment as specified above. Subsequent ovarian cortex autotransplant will be performed by laparoscopy after the patients have been declared cured by their physicians.

Laparoscopic procedures- Upon general anesthesia is induced, attention will be turned to the patient's abdomen where 3-4 0.5 cm skin incisions will be performed (one in the umbilical fold and 2 lateral incisions; possibly, a 4th suprapubic incision). Disposable, bladed, trocars will be inserted in the abdominal cavity. The ovaries will be identified and a unilateral oophorectomy will be performed by retroperitoneal clamping/dissection of the infundibulo-pelvic and utero-ovarian ligaments.

A bipolar electrode will be used to assure accurate hemostasis and irrigation will be performed as needed. Upon retrieval of the trocars from the abdomen, the skin incisions will be reapproximated with 4-0 vycril sutures.

The second laparoscopic procedure will be done to perform autologous ovarian tissue transplant by suturing the thawed cortex fragments to the recipient ovary using 7-0 Prolene (Ethicon, Johnson and Johnson, USA), using the technique described by Silber et al. (Silber et al., 2005; Silber and Gosden, 2007) applied during laparotomy for transplantation.

As the transplanted tissue exhausts its function after the 1st autologous transplant, other laparoscopic procedures might become necessary over the years to transplant the rest of the cryopreserved tissue until no more tissue is available in the cryobank storage.

Freezing Procedure- The process of vitrification will be started in the Operating Room or in the lab within 120 minutes from collection of the sample and will be completed in the University of Tennessee Center for Reproductive Medicine laboratory. The tissue will be subdivided into numerous vials for individual storage/thawing. This will allow selective thawing for autotransplant over multiple procedures, if necessary.

Embryology laboratory procedures- The ovarian tissue that is stored for the patients will be used for autologous transplant. However, other techniques that are performed in the embryology laboratory may be available to the patients in the near future and might represent the best option for fertility preservation in patients with blood-borne cancers (i.e.: leukemia), in whom the risk of re-seeding cancer cells with tissue transplant is high.

Follow-Up Evaluation- Study treatment will include a post-operative visit and following scheduled follow-up visits for the patients' initial disease during which a complete physical exam and psychological evaluation will be conducted, and laboratory testing will be obtained for follicle stimulating hormone (FSH), luteinizing hormone (LH), anti-mullerian hormone (AMH), and Inhibin B.

Visits will be scheduled one month after explant and every 6-12 months until autotransplant of tissue and afterwards.

Laboratory testing, Electrocardiogram (ECG) (12-lead), Bone age, Pelvic ultrasound may be repeated yearly, as part of the patient's scheduled follow-ups. Bone age assessment will stop when a bone age of 18 years is achieved.

Patients who are going to develop ovarian insufficiency prior to or after puberty will undergo estrogen/progesterone therapy as per our institutional protocols.

Follow-up will continue until the patient stays enrolled in the study or until she reaches 40 years of age, or she goes in menopause and does not have, or does not desire, further tissue for transplantation.

Eligibility criteria: Inclusion Criteria:

1. Pre- and post-pubertal patients who are diagnosed with conditions that necessitate chemo- or radiotherapy and wish to preserve their ovarian function.

Exclusion criteria:

1. Patients with acute or chronic conditions that would preclude surgery. These include, but are not limited to, hyper- or hypo-coagulation disorders, lung conditions precluding mechanical ventilation, brain death.
2. Patients for whom the primary oncologist and/or pathologist discourage entering the protocol because of specific condition characteristics. These include, but are not limited to, cancers with high risk of ovarian metastasis such as leukemia and non-Hodgkin lymphoma.
3. Patients with known positive bone marrow for leukemia or solid tumor.
4. Patients whose tumor is in an organ that communicates with the peritoneum and peritoneal sampling at time of primary excision shows evidence of disease.
5. Patients older than 40 years of age.
6. Males.

Primary outcomes:
measure: Resumption of menses
timeFrame: Post-op, after initial explant surgery, & one month after, & every 6-12 months until autotransplant of tissue; through 40 yrs of age/menopause (or, pt.decision to stop earlier)
measure: Initiation of menses
timeFrame: Post-op, after initial explant surgery, & one month after, & every 6-12 months until autotransplant of tissue; through 40 yrs of age/menopause (or, pt.decision to stop earlier)
measure: Completion of puberty
timeFrame: Post-op, after initial explant surgery, & one month after, & every 6-12 months until autotransplant of tissue; through 40 yrs of age/menopause (or, pt.decision to stop earlier)
measure: Fertility
timeFrame: Post-op, after initial explant surgery, & one month after, & every 6-12 months until autotransplant of tissue; through 40 yrs of age/menopause (or, pt.decision to stop earlier)
Secondary outcomes:
measure: Physical UTERINE development
timeFrame: Follow-up at stated intervals, up to 30 years
measure: Physical OVARIAN development
timeFrame: Follow-up at stated intervals, up to 30 years
Other outcomes:
measure: Comparison of biochemical markers, i.e., Estradiol, FSH; LH, AMH; Inhibin B
timeFrame: Follow-up at stated intervals, up to 30 years
Locations:
city: Germantown
country: United States
facility: Methodist/LeBonheur Hospital
state: Tennessee
city: Memphis
country: United States
facility: LeBonheur Children's Hospital
state: Tennessee
city: Memphis
country: United States
facility: Regional One Health Ob-Gyn Clinic
state: Tennessee
city: Memphis
country: United States
facility: Regional One Health, Regional Medical Center, Operating Room
state: Tennessee
city: Memphis
country: United States
facility: Methodist University Hospital
state: Tennessee
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Memphis
country: United States
facility: Baptist Memorial Hospital
state: Tennessee
Study officials:
affiliation: Associate Professor, UTennessee Health Science Center
name: Laura Detti, M.D.
role: PRINCIPAL_INVESTIGATOR
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