Clinical trial NCT02595255: AMH as a Predictor of Infertility Risk in Children With Cancer (CHANCE)
Official title: Antimüllerian Hormone as a Predictor of Future Infertility Risk in Prepubertal/Pubertal Cancer Patients
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Fertility Preservation
Lymphoma
Pediatrics Cancer
Gonadotropin-releasing Hormone Agonist
Keywords: chemotherapy/GnRH (gonadotropin-releasing hormone) analogues/lymphoma/children/fertility
Lead sponsor: Erasme University Hospital
Sponsor class: OTHER
Collaborators: name: Queen Fabiola Children's University Hospital
First posted: 2015-11-03
Enrollment: 275
Sex: FEMALE
Minimum age (years): 3
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The population for this trial is patients between 3 and 14 year old newly diagnosed with cancer or benign diseases treated by chemotherapy and/or pelvic irradiation with high or moderate risk of inducing premature ovarian insufficiency. The "no risk" group includes patients with chronic benign diseases (as pneumology or gastroenterology diseases, congenital hypothyroidism, growth hormone deficiency or RCIU...) or malignancies who will not receive any chemotherapy or other gonadotoxic treatment.

Brief summary: While most of the children spontaneously recover menstruation or experienced normal puberty after chemotherapy, their ovarian reserve may be impaired by treatment inducing future infertility. Fertility preservation is currently proposed for selected prepubertal patients with a high risk of premature ovarian failure after treatment (mostly conditioning regimen for bone marrow transplantation). For patients with low or moderate risks, counselling is very difficult and no fertility preservation procedure is usually proposed for these patients as no marker of the ovarian reserve has been validated in this young population to assess the individual risk.

The primary objective of the study is to prevent long-term treatment-related infertility by detecting the young patients who normally progressed to menarche but have a reduced ovarian reserve. These patients may benefit from particular follow-up and fertility preservation procedure.

Detailed description: In this clinical trial, we will prospectively evaluate the AMH (Antimüllerian Hormone) level before and after treatment (up to 18 years old) in a large cohort of pre- and post-pubertal children treated for cancer. The children enrolled are young patients between 3 and 14 year old who are newly diagnosed with cancer or benign diseases treated by chemotherapy and/or pelvic irradiation. They belong to one of these 3 groups (modified from Wallace et al, 2005):

* High risk
* Moderate/Low risk
* No risk (control group)

Primary endpoint:

Evaluate AMH as a potential biomarker of ovarian reserve in prepubertal/pubertal girl treated by chemotherapy (classified according to the AAD(Alkylating Agent Dose) score)

Secondary endpoints:

* Evaluate the association between the post-treatment ovarian reserve and the AMH pretreatment values in patients considered as moderate or low risk.
* Identify new patients group who may benefit from fertility preservation
* Compare the gonadotoxicity of chemotherapy regimen according to the pubertal status.
* Study the relation between the AMH levels and the pubertal age, menstruation cycle regularity, hormonal levels (FSH (follicle stimulating hormone), œstradiol, and testosterone) and bone age.

Different parameters will be assessed at inclusion, end of the treatment and during the follow-up (every year during the first 3 years and then every 2 years until the end of the study) Oncological outcome The patients will be followed up for progression and survival as per standard local practice.

Ovarian reserve and function:

Ovarian reserve will be evaluated based on hormonal dosages at different times of the study: FSH, AMH, estradiol, testosterone and LH (luteinizing hormone). Menstrual function will be evaluated by collecting information of the pubertal status (spontaneous or induced puberty) and menstrual cycle characteristics

Puberty evaluation:

All children will have an evaluation of the TANNER pubertal stage at 9 years of age (or later if \> 9 years old at the time of inclusion) and once a year until the end of puberty (when patients reach Tanner stage 5). An X-ray of the left hand and wrist will be carried out for bone age evaluation at 9-11 and 13 years old.

Eligibility criteria: Inclusion Criteria:

* Patients from 3 to 14 year old included - Belong to one of these 3 groups (modified from Wallace et al, 2005):

  * High risk : Conditioning therapy for bone marrow transplantation or pelvic irradiation
  * Moderate/Low risk : Pathologies treated with chemotherapy regimen with moderate or low risk of inducing ovarian function insufficiency: AML, osteosarcoma, Ewing sarcoma, neuroblastoma, non-Hodgkin lymphoma, Hodgkin lymphoma, soft tissue sarcoma, ALL, Wilms tumour, retinoblastoma.
  * No risk (control group) : patients with chronic benign diseases or malignancies who don't receive any chemotherapy or other gonadotoxic treatment.

Exclusion Criteria:

* CNS (central nervous system) irradiation, cerebral tumour
* Current or previous ovarian disease/surgery
* Familial history of premature ovarian failure (no iatrogenic or surgical origins)
* Previous known severe chronic disease potentially affecting normal growth or puberty (diseases inducing malnutrition, anorexia, genetic/congenital disorders as Turner, Kallman, BPES(Blepharophimosis, ptosis, and epicanthus inversus syndrome) syndromes, uncontrolled severe diabetes, Cushing Syndrome, auto-immune diseases, cystic fibrosis, severe renal dysfunction)
* Genetic/congenital disorders inducing mental retardation

Primary outcomes:
measure: AMH marker
timeFrame: screening, 1 year after screening, every year during the first 3 year of follow-up, every 2 years until 18 year old
Secondary outcomes:
measure: Premature ovarian failure (POF)
timeFrame: screening, 1 year after screening, every year during the first 3 year of follow-up, every 2 years until 18 year old
measure: Ovarian reserve
timeFrame: screening, 1 year after screening, every year during the first 3 year of follow-up, every 2 years until 18 year old
Other outcomes:
Locations:
city: Montegnée
country: Belgium
facility: Centre Hospitalier Chrétien (CHC)- Clinique de l'espérance
state: Liège
city: Anvers
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Brussels
country: Belgium
facility: Hôpital Universitaire Reine Fabiola (HUDERF)
city: Brussels
country: Belgium
facility: Universitair Ziekenhuis Brussels
city: Ghent
country: Belgium
facility: UZ-Gent
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven
city: Liège
country: Belgium
facility: Centre Hospitalier Régional (CHR)-Citadelle
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lille
country: France
facility: CHRU Lille-Hôpital Jeanne de Flandre
city: Paris
country: France
facility: Hôpital Robert Debré
Study officials:
affiliation: Erasme ULB- Belgium
name: Isabelle Demeestere, PhD
role: STUDY_DIRECTOR
affiliation: Queen Fabiola children's university hospital- Belgium
name: Alina Ferster
role: PRINCIPAL_INVESTIGATOR
affiliation: CHRU Lille, France
name: Christine Decanter
role: PRINCIPAL_INVESTIGATOR
References:
citation: Brougham MF, Crofton PM, Johnson EJ, Evans N, Anderson RA, Wallace WH. Anti-Mullerian hormone is a marker of gonadotoxicity in pre- and postpubertal girls treated for cancer: a prospective study. J Clin Endocrinol Metab. 2012 Jun;97(6):2059-67. doi: 10.1210/jc.2011-3180. Epub 2012 Apr 3.
citation: Wallace WH, Smith AG, Kelsey TW, Edgar AE, Anderson RA. Fertility preservation for girls and young women with cancer: population-based validation of criteria for ovarian tissue cryopreservation. Lancet Oncol. 2014 Sep;15(10):1129-36. doi: 10.1016/S1470-2045(14)70334-1. Epub 2014 Aug 14.
citation: Demeestere I, Simon P, Dedeken L, Moffa F, Tsepelidis S, Brachet C, Delbaere A, Devreker F, Ferster A. Live birth after autograft of ovarian tissue cryopreserved during childhood. Hum Reprod. 2015 Sep;30(9):2107-9. doi: 10.1093/humrep/dev128. Epub 2015 Jun 9.
citation: Imbert R, Moffa F, Tsepelidis S, Simon P, Delbaere A, Devreker F, Dechene J, Ferster A, Veys I, Fastrez M, Englert Y, Demeestere I. Safety and usefulness of cryopreservation of ovarian tissue to preserve fertility: a 12-year retrospective analysis. Hum Reprod. 2014 Sep;29(9):1931-40. doi: 10.1093/humrep/deu158. Epub 2014 Jun 22.