Clinical case 1

Yes surely this patient needs OTC.

Two points to consider: the probability of POI and the probability of minimal disseminated disease (MDD). 1) Indeed, I believe freezing both ovaries has never been done so far, but it has been discussed as a valid option for patients who are at very high risk of gonadotoxicity (eg conditioning treatment before BMT or pelvic radiotherapy) (see Poirot et al, 2025).

2) Let’s look at the literature about MDD and Ewing (this is of importance only at the time of ovarian tissue transplantation of course), with these 2 articles: a) Dolmans et al (2016) did not detect MDD in any of the 26 analyzed samples of sarcoma patients (14 of which had Ewing sarcoma) using sensitive techniques, even from patients who subsequently died and/or those who presented with metastasis (11/26). So this publication was very reassuring. b) Nevertheless, in 2023, a systematic review by Grubliauskaite on MDD in patients with Ewing sarcoma - including the previous mentioned series- reported 3 cases of MDD in the ovary out of 27 patients with Ewing sarcoma, although the initial workup in these patients concluded to a localized disease.

Let’s keep in mind that, among patients under 18 years of age at the time of OTC, in the cohort of my hospital (Jadoul et al, 2017), 24 girls had died, and it is to note that the highest rate of death was in patients with sarcoma, of which almost one out of 4 died. To conclude, OTC is a real hope for those patients, and let us give the possibility to these survivors to become mother one day.

References:

• Dolmans MM, Iwahara Y, Donnez J, Soares M, Vaerman JL, Amorim CA, Poirel H. Evaluation of minimal disseminated disease in cryopreserved ovarian tissue from bone and soft tissue sarcoma patients. Hum Reprod. 2016 Oct;31(10):2292-302. doi: 10.1093/humrep/dew193. Epub 2016 Sep 2. PMID: 27591237.
• Grubliauskaite M, van der Perk MEM, Bos AME, Meijer AJM, Gudleviciene Z, van den Heuvel-Eibrink MM, Rascon J. Minimal Infiltrative Disease Identification in Cryopreserved Ovarian Tissue of Girls with Cancer for Future Use: A Systematic Review. Cancers (Basel). 2023 Aug 22;15(17):4199. doi: 10.3390/cancers15174199. PMID: 37686475; PMCID: PMC10486797.
• Jadoul P, Guilmain A, Squifflet J, Luyckx M, Votino R, Wyns C, Dolmans MM. Efficacy of ovarian tissue cryopreservation for fertility preservation: lessons learned from 545 cases. Hum Reprod. 2017 May 1;32(5):1046-1054. doi: 10.1093/humrep/dex040. PMID: 28333228.

The counselling of adolescent patients on fertility preservation options is complex, and it should be adapted to the patient’s age and maturity. Information should be provided on all available methods for emergency fertility preservation to date, as well as counselling on alternatives to overcome future infertility, even in the cases in which fertility preservation is not possible at the time of the disease. If there is sufficient time available, of about two weeks before the start of chemotherapy treatment, and if the patient has maturity and wish to undergo gynaecological ultrasounds, an evaluation of the ovarian reserve and the feasibility to start hormone stimulation to collect mature eggs could be discussed with immediate initiation of a random-start hormone stimulation protocol. This approach has been described in prospective cohorts, indicating that cryopreservation of mature oocytes is feasibility and preferred by adolescent in selected cases, whenever time is available (Rodriguez-Wallberg et al.,2019).

If time is a constraint, the option of unilateral oophorectomy to cryopreserve ovarian cortical tissue should be presented, as at the patient’s age, OTC for future transplantation is likely to be successful, given an expected high ovarian reserve. In experimental settings, the collection of immature follicles for in vitro maturation has been proposed, and it’s likely that this technique could enhance the efficacy of OTC in the future.

Some patients may prefer not to perform any emergency fertility preservation, and it’s advisable to inform the patients that a future evaluation after the cancer treatment is also possible. The long-term follow-up of girls and adolescents undergoing heavy chemotherapy treatments indicate that a number of patients maintain ovarian function and fertility potential, and that in these cases fertility preservation procedures may be applied also after completion of the cancer treatment (Wikander et al., 2021). Alternatives to become a parent in the future should also be mentioned, and age-adapted decision aids are recommended (Rodriguez-Wallberg et al., 2019).

References:

• Rodriguez-Wallberg KA, Marklund A, Lundberg F, Wikander I, Milenkovic M, Anastacio A, Sergouniotis F, Wånggren K, Ekengren J, Lind T, Borgström B. A prospective study of women and girls undergoing fertility preservation due to oncologic and non-oncologic indications in Sweden-Trends in patients' choices and benefit of the chosen methods after long-term follow up. Acta Obstet Gynecol Scand. 2019;98(5):604-615. PMID: 30723910.
• Wikander I, Lundberg FE, Nilsson H, Borgström B, Rodriguez-Wallberg KA. A Prospective Study on Fertility Preservation in Prepubertal and Adolescent Girls Undergoing Hematological Stem Cell Transplantation. Front Oncol. 2021;11:692834. PMID: 34277437.
• Rodriguez-Wallberg KA, Borgström B, Petersen C, Thurin-Kjellberg A, Mörse H, Giwercman A, Jarfelt M; Work Group UNGA (YOUNG) for the Swedish Association of Local Authorities and Regions, SALAR (Sveriges Kommuner och Landsting, SKL). National guidelines and multilingual age-adapted patient brochures and videos as decision aids for fertility preservation (FP) of children and teenagers with cancer-A multidisciplinary effort to improve children's information and access to FP in Sweden. Acta Obstet Gynecol Scand. 2019;98(5):679-680. PMID: 30793287.