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

Overview

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.

Interventions

• Other No intervention
  No intervention

Primary outcome measures

• AMH marker [Time frame: screening, 1 year after screening, every year during the first 3 year of follow-up, every 2 years until 18 year old]

Secondary outcome measures (2)

• Premature ovarian failure (POF) [Time frame: screening, 1 year after screening, every year during the first 3 year of follow-up, every 2 years until 18 year old]
• Ovarian reserve [Time frame: screening, 1 year after screening, every year during the first 3 year of follow-up, every 2 years until 18 year 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Case-control

Study locations

Belgium · 7 centers

• Centre Hospitalier Chrétien (CHC)- Clinique de l'espérance — Montegnée
• Universitair Ziekenhuis Antwerpen — Antwerp
• Hôpital Universitaire Reine Fabiola (HUDERF) — Brussels
• Universitair Ziekenhuis Brussels — Brussels
• UZ-Gent — Ghent
• Universitair Ziekenhuis Leuven — Leuven
• Centre Hospitalier Régional (CHR)-Citadelle — Liège

France · 3 centers

• Centre Oscar Lambret — Lille
• CHRU Lille-Hôpital Jeanne de Flandre — Lille
• Hôpital Robert Debré — Paris

Publications

• 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. PMID 22472563
• 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. PMID 25130994
• 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. PMID 26062556
• 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. PMID 24958067

Identifiers

NCT: NCT02595255 · CHANCE (CHildren, Amh, caNCEr)

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗