O-088 Effect of low, medium and high risk chemotherapy on the ovarian reserve in children: results of the interim analysis of a prospective multicentric trial (CHANCE)
Authors: Demeestere I , Racape J , Dechene J , Sudour-Bonnange H , Labarque V , Grysole C , Bruno B , Decanter C , Devalck C 
Published: July 2024

Abstract

Study question
How does the ovarian reserve of children diagnosed with cancer recover after chemotherapy that is considered as low or medium risk of future infertility?

Summary answer
The study showed no evidence that low and medium risk treatments impact the future ovarian function in children.

What is known already
Acute premature ovarian insufficiency (POI) post childhood cancer treatment is estimated around 6%, varying with treatment type and age at diagnosis. Long-term risk of treatment-related infertility is challenging to assess in this population as most of the data comes from retrospective trials involving adult cohorts of childhood cancer survivors. Benefit of fertility preservation at diagnosis is evident for high risk patients. However, for low or medium risk patients, the lack of knowledge on treatment effect on the ovarian reserve and on marker reliability in children complicates counselling.

Study design, size, duration
CHANCE is a prospective multicentric observational trial enrolling patients aged between 3 and 14 years at cancer diagnosis. We evaluated factors associated with the risk of future infertility such as hormonal levels, puberty and menstruation, and investigated the fertility preservation strategy. Parameters were assessed at screening, one year post-screening, end of the treatment, and during follow-up (FU) until 18 years of age. An interim analysis was planned considering the duration to reach the final endpoint.

Participants/materials, setting, methods
Between 2014 and 2023, 144 patients were enrolled. Patients were categorized in 3 groups by cumulative equivalent dose of cyclophosphamide (CED) received: &lt;4000mg/m2 (low), 4000 to 8000mg/m2 (medium) and &gt;8000 mg/m2 (high). Ninety-four patients with at least one year post-treatment follow-up were included in this analysis. Mean age at diagnosis was 8.4±4 years and 38% were prepubertal, with no difference between groups (p = 0.06 and 0.26, respectively). The median time of follow-up was 32.7 months.

Main results and the role of chance
Patients were categorized as low (n = 58), medium (n = 18) and high (n = 18) risk based on CED. Sarcoma were most frequent in high risk, while leukemia in low/medium risk groups (p &lt; 0.0001). Fertility preservation was performed in 55.6%, 27.8% and 8.6% in high, medium and low risk group, respectively (p &lt; 0.0001). The majority of them underwent ovarian tissue cryopreservation. POI was defined as induced puberty and/or FSH&gt;25IU/l during FU. POI occurred in 10 out of 18 (55.6%) patients in high risk group, while in no patient in the low/medium risk groups except 1 with disease recurrence. POI was associated with high doses of chemotherapy (p &lt; 0.0001) and increased age (p &lt; 0.007). AMH levels significantly decreased in high and medium risk group during treatment. Recovery occurs in medium but not high risk groups (p = 0.84 and 0.02 between screening and values at 1-2 years and &gt;3 years of FU using repeated measures analysis). Low AMH values (&lt;0.5ng/ml) was observed at 2 years of FU in 14.3%, 28.6% and 69.2% of the patients in low, medium and high risk groups respectively. The impact of treatment, particularly in medium risk group, needs confirmation as around 35% of the patients were still prepubertal at the time of the analysis.

Limitations, reasons for caution
This is an interim analysis of a prospective trial designed to include 275 patients. Data should be cautiously interpreted due to not reaching the calculated optimal power population.

Wider implications of the findings
Our data confirmed that fertility preservation should be offered to all children and adolescent treated with high risk regimen. We did not provide evidence supporting its benefit for low/medium risk pre-pubertal children. For post-pubertal medium risk patients, fertility preservation may be considered during the FU based on patient decision.

Trial registration number
NCT02595255